When Paula Hammond first arrived on MIT’s campus as a first-year student in the early 1980s, she wasn’t sure if she belonged. In fact, as she told an MIT audience yesterday, she felt like “an imposter.”

However, that feeling didn’t last long, as Hammond began to find support among her fellow students and MIT’s faculty. “Community was really important for me, to feel that I belonged, to feel that I had a place here, and I found people who were willing to embrace me and support me,” she said.

Hammond, a world-renowned chemical engineer who has spent most of her academic career at MIT, made her remarks during the 2023-24 James R. Killian Jr. Faculty Achievement Award lecture.

Established in 1971 to honor MIT’s 10th president, James Killian, the Killian Award recognizes extraordinary professional achievements by an MIT faculty member. Hammond was chosen for this year’s award “not only for her tremendous professional achievements and contributions, but also for her genuine warmth and humanity, her thoughtfulness and effective leadership, and her empathy and ethics,” according to the award citation.

“Professor Hammond is a pioneer in nanotechnology research. With a program that extends from basic science to translational research in medicine and energy, she has introduced new approaches for the design and development of complex drug delivery systems for cancer treatment and noninvasive imaging,” said Mary Fuller, chair of MIT’s faculty and a professor of literature, who presented the award. “As her colleagues, we are delighted to celebrate her career today.”

In January, Hammond began serving as MIT’s vice provost for faculty. Before that, she chaired the Department of Chemical Engineering for eight years, and she was named an Institute Professor in 2021.

A versatile technique

Hammond, who grew up in Detroit, credits her parents with instilling a love of science. Her father was one of very few Black PhDs in biochemistry at the time, while her mother earned a master’s degree in nursing from Howard University and founded the nursing school at Wayne County Community College. “That provided a huge amount of opportunity for women in the area of Detroit, including women of color,” Hammond noted.

After earning her bachelor’s degree from MIT in 1984, Hammond worked as an engineer before returning to the Institute as a graduate student, earning her PhD in 1993. After a two-year postdoc at Harvard University, she returned to join the MIT faculty in 1995.

At the heart of Hammond’s research is a technique she developed to create thin films that can essentially “shrink-wrap” nanoparticles. By tuning the chemical composition of these films, the particles can be customized to deliver drugs or nucleic acids and to target specific cells in the body, including cancer cells.

To make these films, Hammond begins by layering positively charged polymers onto a negatively charged surface. Then, more layers can be added, alternating positively and negatively charged polymers. Each of these layers may contain drugs or other useful molecules, such as DNA or RNA. Some of these films contain hundreds of layers, others just one, making them useful for a wide range of applications.

“What’s nice about the layer-by-layer process is I can choose a group of degradable polymers that are nicely biocompatible, and I can alternate them with our drug materials. This means that I can build up thin film layers that contain different drugs at different points within the film,” Hammond said. “Then, when the film degrades, it can release those drugs in reverse order. This is enabling us to create complex, multidrug films, using a simple water-based technique.”

Hammond described how these layer-by-layer films can be used to promote bone growth, in an application that could help people born with congenital bone defects or people who experience traumatic injuries.

For that use, her lab has created films with layers of two proteins. One of these, BMP-2, is a protein that interacts with adult stem cells and induces them to differentiate into bone cells, generating new bone. The second is a growth factor called VEGF, which stimulates the growth of new blood vessels that help bone to regenerate. These layers are applied to a very thin tissue scaffold that can be implanted at the injury site.

Hammond and her students designed the coating so that once implanted, it would release VEGF early, over a week or so, and continue releasing BMP-2 for up to 40 days. In a study of mice, they found that this tissue scaffold stimulated the growth of new bone that was nearly indistinguishable from natural bone.

Targeting cancer

As a member of MIT’s Koch Institute for Integrative Cancer Research, Hammond has also developed layer-by-layer coatings that can improve the performance of nanoparticles used for cancer drug delivery, such as liposomes or nanoparticles made from a polymer called PLGA.

“We have a broad range of drug carriers that we can wrap this way. I think of them like a gobstopper, where there are all those different layers of candy and they dissolve one at a time,” Hammond said.

Using this approach, Hammond has created particles that can deliver a one-two punch to cancer cells. First, the particles release a dose of a nucleic acid such as short interfering RNA (siRNA), which can turn off a cancerous gene, or microRNA, which can activate tumor suppressor genes. Then, the particles release a chemotherapy drug such as cisplatin, to which the cells are now more vulnerable.

The particles also include a negatively charged outer “stealth layer” that protects them from being broken down in the bloodstream before they can reach their targets. This outer layer can also be modified to help the particles get taken up by cancer cells, by incorporating molecules that bind to proteins that are abundant on tumor cells.

In more recent work, Hammond has begun developing nanoparticles that can target ovarian cancer and help prevent recurrence of the disease after chemotherapy. In about 70 percent of ovarian cancer patients, the first round of treatment is highly effective, but tumors recur in about 85 percent of those cases, and these new tumors are usually highly drug resistant.

By altering the type of coating applied to drug-delivering nanoparticles, Hammond has found that the particles can be designed to either get inside tumor cells or stick to their surfaces. Using particles that stick to the cells, she has designed a treatment that could help to jumpstart a patient’s immune response to any recurrent tumor cells.

“With ovarian cancer, very few immune cells exist in that space, and because they don’t have a lot of immune cells present, it’s very difficult to rev up an immune response,” she said. “However, if we can deliver a molecule to neighboring cells, those few that are present, and get them revved up, then we might be able to do something.”

To that end, she designed nanoparticles that deliver IL-12, a cytokine that stimulates nearby T cells to spring into action and begin attacking tumor cells. In a study of mice, she found that this treatment induced a long-term memory T-cell response that prevented recurrence of ovarian cancer.

Hammond closed her lecture by describing the impact that the Institute has had on her throughout her career.

“It’s been a transformative experience,” she said. “I really think of this place as special because it brings people together and enables us to do things together that we couldn’t do alone. And it is that support we get from our friends, our colleagues, and our students that really makes things possible.”

© Photo: Jake Belcher

Many vaccines, including vaccines for hepatitis B and whooping cough, consist of fragments of viral or bacterial proteins. These vaccines often include other molecules called adjuvants, which help to boost the immune system’s response to the protein.

Most of these adjuvants consist of aluminum salts or other molecules that provoke a nonspecific immune response. A team of MIT researchers has now shown that a type of nanoparticle called a metal organic framework (MOF) can also provoke a strong immune response, by activating the innate immune system — the body’s first line of defense against any pathogen — through cell proteins called toll-like receptors.

In a study of mice, the researchers showed that this MOF could successfully encapsulate and deliver part of the SARS-CoV-2 spike protein, while also acting as an adjuvant once the MOF is broken down inside cells.

While more work would be needed to adapt these particles for use as vaccines, the study demonstrates that this type of structure can be useful for generating a strong immune response, the researchers say.

“Understanding how the drug delivery vehicle can enhance an adjuvant immune response is something that could be very helpful in designing new vaccines,” says Ana Jaklenec, a principal investigator at MIT’s Koch Institute for Integrative Cancer Research and one of the senior authors of the new study.

Robert Langer, an MIT Institute Professor and member of the Koch Institute, and Dan Barouch, director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center and a professor at Harvard Medical School, are also senior authors of the paper, which appears today in Science Advances. The paper’s lead author is former MIT postdoc and Ibn Khaldun Fellow Shahad Alsaiari.

Immune activation

In this study, the researchers focused on a MOF called ZIF-8, which consists of a lattice of tetrahedral units made up of a zinc ion attached to four molecules of imidazole, an organic compound. Previous work has shown that ZIF-8 can significantly boost immune responses, but it wasn’t known exactly how this particle activates the immune system.

To try to figure that out, the MIT team created an experimental vaccine consisting of the SARS-CoV-2 receptor-binding protein (RBD) embedded within ZIF-8 particles. These particles are between 100 and 200 nanometers in diameter, a size that allows them to get into the body’s lymph nodes directly or through immune cells such as macrophages.

Once the particles enter the cells, the MOFs are broken down, releasing the viral proteins. The researchers found that the imidazole components then activate toll-like receptors (TLRs), which help to stimulate the innate immune response.

“This process is analogous to establishing a covert operative team at the molecular level to transport essential elements of the Covid-19 virus to the body’s immune system, where they can activate specific immune responses to boost vaccine efficacy,” Alsaiari says.

RNA sequencing of cells from the lymph nodes showed that mice vaccinated with ZIF-8 particles carrying the viral protein strongly activated a TLR pathway known as TLR-7, which led to greater production of cytokines and other molecules involved in inflammation.

Mice vaccinated with these particles generated a much stronger response to the viral protein than mice that received the protein on its own.

“Not only are we delivering the protein in a more controlled way through a nanoparticle, but the compositional structure of this particle is also acting as an adjuvant,” Jaklenec says. “We were able to achieve very specific responses to the Covid protein, and with a dose-sparing effect compared to using the protein by itself to vaccinate.”

Vaccine access

While this study and others have demonstrated ZIF-8’s immunogenic ability, more work needs to be done to evaluate the particles’ safety and potential to be scaled up for large-scale manufacturing. If ZIF-8 is not developed as a vaccine carrier, the findings from the study should help to guide researchers in developing similar nanoparticles that could be used to deliver subunit vaccines, Jaklenec says.

“Most subunit vaccines usually have two separate components: an antigen and an adjuvant,” Jaklenec says. “Designing new vaccines that utilize nanoparticles with specific chemical moieties which not only aid in antigen delivery but can also activate particular immune pathways have the potential to enhance vaccine potency.”

One advantage to developing a subunit vaccine for Covid-19 is that such vaccines are usually easier and cheaper to manufacture than mRNA vaccines, which could make it easier to distribute them around the world, the researchers say.

“Subunit vaccines have been around for a long time, and they tend to be cheaper to produce, so that opens up more access to vaccines, especially in times of pandemic,” Jaklenec says.

The research was funded by Ibn Khaldun Fellowships for Saudi Arabian Women and in part by the Koch Institute Support (core) Grant from the U.S. National Cancer Institute.

© Image: Courtesy of the researchers

A team of MIT researchers will lead a $65.67 million effort, awarded by the U.S. Advanced Research Projects Agency for Health (ARPA-H), to develop ingestible devices that may one day be used to treat diabetes, obesity, and other conditions through oral delivery of mRNA. Such devices could potentially be deployed for needle-free delivery of mRNA vaccines as well.

The five-year project also aims to develop electroceuticals, a new form of ingestible therapies based on electrical stimulation of the body’s own hormones and neural signaling. If successful, this approach could lead to new treatments for a variety of metabolic disorders.

“We know that the oral route is generally the preferred route of administration for both patients and health care providers,” says Giovanni Traverso, an associate professor of mechanical engineering at MIT and a gastroenterologist at Brigham and Women’s Hospital. “Our primary focus is on disorders of metabolism because they affect a lot of people, but the platforms we’re developing could be applied very broadly.”

Traverso is the principal investigator for the project, which also includes Robert Langer, MIT Institute Professor, and Anantha Chandrakasan, dean of the MIT School of Engineering and the Vannevar Bush Professor of Electrical Engineering and Computer Science. As part of the project, the MIT team will collaborate with investigators from Brigham and Women’s Hospital, New York University, and the University of Colorado School of Medicine.

Over the past several years, Traverso’s and Langer’s labs have designed many types of ingestible devices that can deliver drugs to the GI tract. This approach could be especially useful for protein drugs and nucleic acids, which typically can’t be given orally because they break down in the acidic environment of the digestive tract.

Messenger RNA has already proven useful as a vaccine, directing cells to produce fragments of viral proteins that trigger an immune response. Delivering mRNA to cells also holds potential to stimulate production of therapeutic molecules to treat a variety of diseases. In this project, the researchers plan to focus on metabolic diseases such as diabetes.

“What mRNA can do is enable the potential for dosing therapies that are very difficult to dose today, or provide longer-term coverage by essentially creating an internal factory that produces a therapy for a prolonged period,” Traverso says.

In the mRNA portion of the project, the research team intends to identify lipid and polymer nanoparticle formulations that can most effectively deliver mRNA to cells, using machine learning to help identify the best candidates. They will also develop and test ingestible devices to carry the mRNA-nanoparticle payload, with the goal of running a clinical trial in the final year of the five-year project.

The work will build on research that Traverso’s lab has already begun. In 2022, Traverso and his colleagues reported that they could deliver mRNA in capsules that inject mRNA-nanoparticle complexes into the lining of the stomach.

The other branch of the project will focus on ingestible devices that can deliver a small electrical current to the lining of the stomach. In a study published last year, Traverso’s lab demonstrated this approach for the first time, using a capsule coated with electrodes that apply an electrical current to cells of the stomach. In animal studies, they found that this stimulation boosted production of ghrelin, a hormone that stimulates appetite.

Traverso envisions that this type of treatment could potentially replace or complement some of the existing drugs used to prevent nausea and stimulate appetite in people with anorexia or cachexia (loss of body mass that can occur in patients with cancer or other chronic diseases). The researchers also hope to develop ways to stimulate production of GLP-1, a hormone that is used to help manage diabetes and promote weight loss.

“What this approach starts to do is potentially maximize our ability to treat disease without administering a new drug, but instead by simply modulating the body’s own systems through electrical stimulation,” Traverso says.

At MIT, Langer will help to develop nanoparticles for mRNA delivery, and Chandrakasan will work on ways to reduce energy consumption and miniaturize the electronic functions of the capsules, including secure communication, stimulation, and power generation.

The Brigham and Women’s Hospital’s portion of the project will be co-led by Traverso, Ameya Kirtane, Jason Li, and Peter Chai, who will amplify efforts on the formulation and stabilization of the mRNA nanoparticles, engineering of the ingestible devices, and running of clinical trials. At NYU, the effort will be led by assistant professor of bioengineering Khalil Ramadi SM ’16, PhD ’19, focusing on biological characterization of the effects of electrical stimulation. Researchers at the University of Colorado, led by Matthew Wynia and Eric G. Campbell of the CU Center for Bioethics and Humanities, will focus on exploring the ethical dimensions and public perceptions of these types of biomedical interventions.

“We felt like we had an opportunity here not only to do fundamental engineering science and early-stage clinical trials, but also to start to understand the data behind some of the ethical implications and public perceptions of these technologies through this broad collaboration,” Traverso says.

The project described here is supported by ARPA-H under award number D24AC00040-00. The content of this announcement does not necessarily represent the official views of the Advanced Research Projects Agency for Health.

© Image: Courtesy of MechE

When Paula Hammond first arrived on MIT’s campus as a first-year student in the early 1980s, she wasn’t sure if she belonged. In fact, as she told an MIT audience yesterday, she felt like “an imposter.”

However, that feeling didn’t last long, as Hammond began to find support among her fellow students and MIT’s faculty. “Community was really important for me, to feel that I belonged, to feel that I had a place here, and I found people who were willing to embrace me and support me,” she said.

Hammond, a world-renowned chemical engineer who has spent most of her academic career at MIT, made her remarks during the 2023-24 James R. Killian Jr. Faculty Achievement Award lecture.

Established in 1971 to honor MIT’s 10th president, James Killian, the Killian Award recognizes extraordinary professional achievements by an MIT faculty member. Hammond was chosen for this year’s award “not only for her tremendous professional achievements and contributions, but also for her genuine warmth and humanity, her thoughtfulness and effective leadership, and her empathy and ethics,” according to the award citation.

“Professor Hammond is a pioneer in nanotechnology research. With a program that extends from basic science to translational research in medicine and energy, she has introduced new approaches for the design and development of complex drug delivery systems for cancer treatment and noninvasive imaging,” said Mary Fuller, chair of MIT’s faculty and a professor of literature, who presented the award. “As her colleagues, we are delighted to celebrate her career today.”

In January, Hammond began serving as MIT’s vice provost for faculty. Before that, she chaired the Department of Chemical Engineering for eight years, and she was named an Institute Professor in 2021.

A versatile technique

Hammond, who grew up in Detroit, credits her parents with instilling a love of science. Her father was one of very few Black PhDs in biochemistry at the time, while her mother earned a master’s degree in nursing from Howard University and founded the nursing school at Wayne County Community College. “That provided a huge amount of opportunity for women in the area of Detroit, including women of color,” Hammond noted.

After earning her bachelor’s degree from MIT in 1984, Hammond worked as an engineer before returning to the Institute as a graduate student, earning her PhD in 1993. After a two-year postdoc at Harvard University, she returned to join the MIT faculty in 1995.

At the heart of Hammond’s research is a technique she developed to create thin films that can essentially “shrink-wrap” nanoparticles. By tuning the chemical composition of these films, the particles can be customized to deliver drugs or nucleic acids and to target specific cells in the body, including cancer cells.

To make these films, Hammond begins by layering positively charged polymers onto a negatively charged surface. Then, more layers can be added, alternating positively and negatively charged polymers. Each of these layers may contain drugs or other useful molecules, such as DNA or RNA. Some of these films contain hundreds of layers, others just one, making them useful for a wide range of applications.

“What’s nice about the layer-by-layer process is I can choose a group of degradable polymers that are nicely biocompatible, and I can alternate them with our drug materials. This means that I can build up thin film layers that contain different drugs at different points within the film,” Hammond said. “Then, when the film degrades, it can release those drugs in reverse order. This is enabling us to create complex, multidrug films, using a simple water-based technique.”

Hammond described how these layer-by-layer films can be used to promote bone growth, in an application that could help people born with congenital bone defects or people who experience traumatic injuries.

For that use, her lab has created films with layers of two proteins. One of these, BMP-2, is a protein that interacts with adult stem cells and induces them to differentiate into bone cells, generating new bone. The second is a growth factor called VEGF, which stimulates the growth of new blood vessels that help bone to regenerate. These layers are applied to a very thin tissue scaffold that can be implanted at the injury site.

Hammond and her students designed the coating so that once implanted, it would release VEGF early, over a week or so, and continue releasing BMP-2 for up to 40 days. In a study of mice, they found that this tissue scaffold stimulated the growth of new bone that was nearly indistinguishable from natural bone.

Targeting cancer

As a member of MIT’s Koch Institute for Integrative Cancer Research, Hammond has also developed layer-by-layer coatings that can improve the performance of nanoparticles used for cancer drug delivery, such as liposomes or nanoparticles made from a polymer called PLGA.

“We have a broad range of drug carriers that we can wrap this way. I think of them like a gobstopper, where there are all those different layers of candy and they dissolve one at a time,” Hammond said.

Using this approach, Hammond has created particles that can deliver a one-two punch to cancer cells. First, the particles release a dose of a nucleic acid such as short interfering RNA (siRNA), which can turn off a cancerous gene, or microRNA, which can activate tumor suppressor genes. Then, the particles release a chemotherapy drug such as cisplatin, to which the cells are now more vulnerable.

The particles also include a negatively charged outer “stealth layer” that protects them from being broken down in the bloodstream before they can reach their targets. This outer layer can also be modified to help the particles get taken up by cancer cells, by incorporating molecules that bind to proteins that are abundant on tumor cells.

In more recent work, Hammond has begun developing nanoparticles that can target ovarian cancer and help prevent recurrence of the disease after chemotherapy. In about 70 percent of ovarian cancer patients, the first round of treatment is highly effective, but tumors recur in about 85 percent of those cases, and these new tumors are usually highly drug resistant.

By altering the type of coating applied to drug-delivering nanoparticles, Hammond has found that the particles can be designed to either get inside tumor cells or stick to their surfaces. Using particles that stick to the cells, she has designed a treatment that could help to jumpstart a patient’s immune response to any recurrent tumor cells.

“With ovarian cancer, very few immune cells exist in that space, and because they don’t have a lot of immune cells present, it’s very difficult to rev up an immune response,” she said. “However, if we can deliver a molecule to neighboring cells, those few that are present, and get them revved up, then we might be able to do something.”

To that end, she designed nanoparticles that deliver IL-12, a cytokine that stimulates nearby T cells to spring into action and begin attacking tumor cells. In a study of mice, she found that this treatment induced a long-term memory T-cell response that prevented recurrence of ovarian cancer.

Hammond closed her lecture by describing the impact that the Institute has had on her throughout her career.

“It’s been a transformative experience,” she said. “I really think of this place as special because it brings people together and enables us to do things together that we couldn’t do alone. And it is that support we get from our friends, our colleagues, and our students that really makes things possible.”

© Photo: Jake Belcher

Many vaccines, including vaccines for hepatitis B and whooping cough, consist of fragments of viral or bacterial proteins. These vaccines often include other molecules called adjuvants, which help to boost the immune system’s response to the protein.

Most of these adjuvants consist of aluminum salts or other molecules that provoke a nonspecific immune response. A team of MIT researchers has now shown that a type of nanoparticle called a metal organic framework (MOF) can also provoke a strong immune response, by activating the innate immune system — the body’s first line of defense against any pathogen — through cell proteins called toll-like receptors.

In a study of mice, the researchers showed that this MOF could successfully encapsulate and deliver part of the SARS-CoV-2 spike protein, while also acting as an adjuvant once the MOF is broken down inside cells.

While more work would be needed to adapt these particles for use as vaccines, the study demonstrates that this type of structure can be useful for generating a strong immune response, the researchers say.

“Understanding how the drug delivery vehicle can enhance an adjuvant immune response is something that could be very helpful in designing new vaccines,” says Ana Jaklenec, a principal investigator at MIT’s Koch Institute for Integrative Cancer Research and one of the senior authors of the new study.

Robert Langer, an MIT Institute Professor and member of the Koch Institute, and Dan Barouch, director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center and a professor at Harvard Medical School, are also senior authors of the paper, which appears today in Science Advances. The paper’s lead author is former MIT postdoc and Ibn Khaldun Fellow Shahad Alsaiari.

Immune activation

In this study, the researchers focused on a MOF called ZIF-8, which consists of a lattice of tetrahedral units made up of a zinc ion attached to four molecules of imidazole, an organic compound. Previous work has shown that ZIF-8 can significantly boost immune responses, but it wasn’t known exactly how this particle activates the immune system.

To try to figure that out, the MIT team created an experimental vaccine consisting of the SARS-CoV-2 receptor-binding protein (RBD) embedded within ZIF-8 particles. These particles are between 100 and 200 nanometers in diameter, a size that allows them to get into the body’s lymph nodes directly or through immune cells such as macrophages.

Once the particles enter the cells, the MOFs are broken down, releasing the viral proteins. The researchers found that the imidazole components then activate toll-like receptors (TLRs), which help to stimulate the innate immune response.

“This process is analogous to establishing a covert operative team at the molecular level to transport essential elements of the Covid-19 virus to the body’s immune system, where they can activate specific immune responses to boost vaccine efficacy,” Alsaiari says.

RNA sequencing of cells from the lymph nodes showed that mice vaccinated with ZIF-8 particles carrying the viral protein strongly activated a TLR pathway known as TLR-7, which led to greater production of cytokines and other molecules involved in inflammation.

Mice vaccinated with these particles generated a much stronger response to the viral protein than mice that received the protein on its own.

“Not only are we delivering the protein in a more controlled way through a nanoparticle, but the compositional structure of this particle is also acting as an adjuvant,” Jaklenec says. “We were able to achieve very specific responses to the Covid protein, and with a dose-sparing effect compared to using the protein by itself to vaccinate.”

Vaccine access

While this study and others have demonstrated ZIF-8’s immunogenic ability, more work needs to be done to evaluate the particles’ safety and potential to be scaled up for large-scale manufacturing. If ZIF-8 is not developed as a vaccine carrier, the findings from the study should help to guide researchers in developing similar nanoparticles that could be used to deliver subunit vaccines, Jaklenec says.

“Most subunit vaccines usually have two separate components: an antigen and an adjuvant,” Jaklenec says. “Designing new vaccines that utilize nanoparticles with specific chemical moieties which not only aid in antigen delivery but can also activate particular immune pathways have the potential to enhance vaccine potency.”

One advantage to developing a subunit vaccine for Covid-19 is that such vaccines are usually easier and cheaper to manufacture than mRNA vaccines, which could make it easier to distribute them around the world, the researchers say.

“Subunit vaccines have been around for a long time, and they tend to be cheaper to produce, so that opens up more access to vaccines, especially in times of pandemic,” Jaklenec says.

The research was funded by Ibn Khaldun Fellowships for Saudi Arabian Women and in part by the Koch Institute Support (core) Grant from the U.S. National Cancer Institute.

© Image: Courtesy of the researchers

A team of MIT researchers will lead a $65.67 million effort, awarded by the U.S. Advanced Research Projects Agency for Health (ARPA-H), to develop ingestible devices that may one day be used to treat diabetes, obesity, and other conditions through oral delivery of mRNA. Such devices could potentially be deployed for needle-free delivery of mRNA vaccines as well.

The five-year project also aims to develop electroceuticals, a new form of ingestible therapies based on electrical stimulation of the body’s own hormones and neural signaling. If successful, this approach could lead to new treatments for a variety of metabolic disorders.

“We know that the oral route is generally the preferred route of administration for both patients and health care providers,” says Giovanni Traverso, an associate professor of mechanical engineering at MIT and a gastroenterologist at Brigham and Women’s Hospital. “Our primary focus is on disorders of metabolism because they affect a lot of people, but the platforms we’re developing could be applied very broadly.”

Traverso is the principal investigator for the project, which also includes Robert Langer, MIT Institute Professor, and Anantha Chandrakasan, dean of the MIT School of Engineering and the Vannevar Bush Professor of Electrical Engineering and Computer Science. As part of the project, the MIT team will collaborate with investigators from Brigham and Women’s Hospital, New York University, and the University of Colorado School of Medicine.

Over the past several years, Traverso’s and Langer’s labs have designed many types of ingestible devices that can deliver drugs to the GI tract. This approach could be especially useful for protein drugs and nucleic acids, which typically can’t be given orally because they break down in the acidic environment of the digestive tract.

Messenger RNA has already proven useful as a vaccine, directing cells to produce fragments of viral proteins that trigger an immune response. Delivering mRNA to cells also holds potential to stimulate production of therapeutic molecules to treat a variety of diseases. In this project, the researchers plan to focus on metabolic diseases such as diabetes.

“What mRNA can do is enable the potential for dosing therapies that are very difficult to dose today, or provide longer-term coverage by essentially creating an internal factory that produces a therapy for a prolonged period,” Traverso says.

In the mRNA portion of the project, the research team intends to identify lipid and polymer nanoparticle formulations that can most effectively deliver mRNA to cells, using machine learning to help identify the best candidates. They will also develop and test ingestible devices to carry the mRNA-nanoparticle payload, with the goal of running a clinical trial in the final year of the five-year project.

The work will build on research that Traverso’s lab has already begun. In 2022, Traverso and his colleagues reported that they could deliver mRNA in capsules that inject mRNA-nanoparticle complexes into the lining of the stomach.

The other branch of the project will focus on ingestible devices that can deliver a small electrical current to the lining of the stomach. In a study published last year, Traverso’s lab demonstrated this approach for the first time, using a capsule coated with electrodes that apply an electrical current to cells of the stomach. In animal studies, they found that this stimulation boosted production of ghrelin, a hormone that stimulates appetite.

Traverso envisions that this type of treatment could potentially replace or complement some of the existing drugs used to prevent nausea and stimulate appetite in people with anorexia or cachexia (loss of body mass that can occur in patients with cancer or other chronic diseases). The researchers also hope to develop ways to stimulate production of GLP-1, a hormone that is used to help manage diabetes and promote weight loss.

“What this approach starts to do is potentially maximize our ability to treat disease without administering a new drug, but instead by simply modulating the body’s own systems through electrical stimulation,” Traverso says.

At MIT, Langer will help to develop nanoparticles for mRNA delivery, and Chandrakasan will work on ways to reduce energy consumption and miniaturize the electronic functions of the capsules, including secure communication, stimulation, and power generation.

The Brigham and Women’s Hospital’s portion of the project will be co-led by Traverso, Ameya Kirtane, Jason Li, and Peter Chai, who will amplify efforts on the formulation and stabilization of the mRNA nanoparticles, engineering of the ingestible devices, and running of clinical trials. At NYU, the effort will be led by assistant professor of bioengineering Khalil Ramadi SM ’16, PhD ’19, focusing on biological characterization of the effects of electrical stimulation. Researchers at the University of Colorado, led by Matthew Wynia and Eric G. Campbell of the CU Center for Bioethics and Humanities, will focus on exploring the ethical dimensions and public perceptions of these types of biomedical interventions.

“We felt like we had an opportunity here not only to do fundamental engineering science and early-stage clinical trials, but also to start to understand the data behind some of the ethical implications and public perceptions of these technologies through this broad collaboration,” Traverso says.

The project described here is supported by ARPA-H under award number D24AC00040-00. The content of this announcement does not necessarily represent the official views of the Advanced Research Projects Agency for Health.

© Image: Courtesy of MechE

Using a virus-like delivery particle made from DNA, researchers from MIT and the Ragon Institute of MGH, MIT, and Harvard have created a vaccine that can induce a strong antibody response against SARS-CoV-2.

The vaccine, which has been tested in mice, consists of a DNA scaffold that carries many copies of a viral antigen. This type of vaccine, known as a particulate vaccine, mimics the structure of a virus. Most previous work on particulate vaccines has relied on protein scaffolds, but the proteins used in those vaccines tend to generate an unnecessary immune response that can distract the immune system from the target.

In the mouse study, the researchers found that the DNA scaffold does not induce an immune response, allowing the immune system to focus its antibody response on the target antigen.

“DNA, we found in this work, does not elicit antibodies that may distract away from the protein of interest,” says Mark Bathe, an MIT professor of biological engineering. “What you can imagine is that your B cells and immune system are being fully trained by that target antigen, and that’s what you want — for your immune system to be laser-focused on the antigen of interest.”

This approach, which strongly stimulates B cells (the cells that produce antibodies), could make it easier to develop vaccines against viruses that have been difficult to target, including HIV and influenza, as well as SARS-CoV-2, the researchers say. Unlike T cells, which are stimulated by other types of vaccines, these B cells can persist for decades, offering long-term protection.

“We’re interested in exploring whether we can teach the immune system to deliver higher levels of immunity against pathogens that resist conventional vaccine approaches, like flu, HIV, and SARS-CoV-2,” says Daniel Lingwood, an associate professor at Harvard Medical School and a principal investigator at the Ragon Institute. “This idea of decoupling the response against the target antigen from the platform itself is a potentially powerful immunological trick that one can now bring to bear to help those immunological targeting decisions move in a direction that is more focused.”

Bathe, Lingwood, and Aaron Schmidt, an associate professor at Harvard Medical School and principal investigator at the Ragon Institute, are the senior authors of the paper, which appears today in Nature Communications. The paper’s lead authors are Eike-Christian Wamhoff, a former MIT postdoc; Larance Ronsard, a Ragon Institute postdoc; Jared Feldman, a former Harvard University graduate student; Grant Knappe, an MIT graduate student; and Blake Hauser, a former Harvard graduate student. 

Mimicking viruses

Particulate vaccines usually consist of a protein nanoparticle, similar in structure to a virus, that can carry many copies of a viral antigen. This high density of antigens can lead to a stronger immune response than traditional vaccines because the body sees it as similar to an actual virus. Particulate vaccines have been developed for a handful of pathogens, including hepatitis B and human papillomavirus, and a particulate vaccine for SARS-CoV-2 has been approved for use in South Korea.

These vaccines are especially good at activating B cells, which produce antibodies specific to the vaccine antigen.

“Particulate vaccines are of great interest for many in immunology because they give you robust humoral immunity, which is antibody-based immunity, which is differentiated from the T-cell-based immunity that the mRNA vaccines seem to elicit more strongly,” Bathe says.

A potential drawback to this kind of vaccine, however, is that the proteins used for the scaffold often stimulate the body to produce antibodies targeting the scaffold. This can distract the immune system and prevent it from launching as robust a response as one would like, Bathe says.

“To neutralize the SARS-CoV-2 virus, you want to have a vaccine that generates antibodies toward the receptor binding domain portion of the virus’ spike protein,” he says. “When you display that on a protein-based particle, what happens is your immune system recognizes not only that receptor binding domain protein, but all the other proteins that are irrelevant to the immune response you’re trying to elicit.”

Another potential drawback is that if the same person receives more than one vaccine carried by the same protein scaffold, for example, SARS-CoV-2 and then influenza, their immune system would likely respond right away to the protein scaffold, having already been primed to react to it. This could weaken the immune response to the antigen carried by the second vaccine.

“If you want to apply that protein-based particle to immunize against a different virus like influenza, then your immune system can be addicted to the underlying protein scaffold that it’s already seen and developed an immune response toward,” Bathe says. “That can hypothetically diminish the quality of your antibody response for the actual antigen of interest.”

As an alternative, Bathe’s lab has been developing scaffolds made using DNA origami, a method that offers precise control over the structure of synthetic DNA and allows researchers to attach a variety of molecules, such as viral antigens, at specific locations.

In a 2020 study, Bathe and Darrell Irvine, an MIT professor of biological engineering and of materials science and engineering, showed that a DNA scaffold carrying 30 copies of an HIV antigen could generate a strong antibody response in B cells grown in the lab. This type of structure is optimal for activating B cells because it closely mimics the structure of nano-sized viruses, which display many copies of viral proteins in their surfaces.

“This approach builds off of a fundamental principle in B-cell antigen recognition, which is that if you have an arrayed display of the antigen, that promotes B-cell responses and gives better quantity and quality of antibody output,” Lingwood says.

“Immunologically silent”

In the new study, the researchers swapped in an antigen consisting of the receptor binding protein of the spike protein from the original strain of SARS-CoV-2. When they gave the vaccine to mice, they found that the mice generated high levels of antibodies to the spike protein but did not generate any to the DNA scaffold.

In contrast, a vaccine based on a scaffold protein called ferritin, coated with SARS-CoV-2 antigens, generated many antibodies against ferritin as well as SARS-CoV-2.

“The DNA nanoparticle itself is immunogenically silent,” Lingwood says. “If you use a protein-based platform, you get equally high titer antibody responses to the platform and to the antigen of interest, and that can complicate repeated usage of that platform because you’ll develop high affinity immune memory against it.”

Reducing these off-target effects could also help scientists reach the goal of developing a vaccine that would induce broadly neutralizing antibodies to any variant of SARS-CoV-2, or even to all sarbecoviruses, the subgenus of virus that includes SARS-CoV-2 as well as the viruses that cause SARS and MERS.

To that end, the researchers are now exploring whether a DNA scaffold with many different viral antigens attached could induce broadly neutralizing antibodies against SARS-CoV-2 and related viruses. 

The research was primarily funded by the National Institutes of Health, the National Science Foundation, and the Fast Grants program.

© Credit: The Bathe Lab

When Paula Hammond first arrived on MIT’s campus as a first-year student in the early 1980s, she wasn’t sure if she belonged. In fact, as she told an MIT audience yesterday, she felt like “an imposter.”

However, that feeling didn’t last long, as Hammond began to find support among her fellow students and MIT’s faculty. “Community was really important for me, to feel that I belonged, to feel that I had a place here, and I found people who were willing to embrace me and support me,” she said.

Hammond, a world-renowned chemical engineer who has spent most of her academic career at MIT, made her remarks during the 2023-24 James R. Killian Jr. Faculty Achievement Award lecture.

Established in 1971 to honor MIT’s 10th president, James Killian, the Killian Award recognizes extraordinary professional achievements by an MIT faculty member. Hammond was chosen for this year’s award “not only for her tremendous professional achievements and contributions, but also for her genuine warmth and humanity, her thoughtfulness and effective leadership, and her empathy and ethics,” according to the award citation.

“Professor Hammond is a pioneer in nanotechnology research. With a program that extends from basic science to translational research in medicine and energy, she has introduced new approaches for the design and development of complex drug delivery systems for cancer treatment and noninvasive imaging,” said Mary Fuller, chair of MIT’s faculty and a professor of literature, who presented the award. “As her colleagues, we are delighted to celebrate her career today.”

In January, Hammond began serving as MIT’s vice provost for faculty. Before that, she chaired the Department of Chemical Engineering for eight years, and she was named an Institute Professor in 2021.

A versatile technique

Hammond, who grew up in Detroit, credits her parents with instilling a love of science. Her father was one of very few Black PhDs in biochemistry at the time, while her mother earned a master’s degree in nursing from Howard University and founded the nursing school at Wayne County Community College. “That provided a huge amount of opportunity for women in the area of Detroit, including women of color,” Hammond noted.

After earning her bachelor’s degree from MIT in 1984, Hammond worked as an engineer before returning to the Institute as a graduate student, earning her PhD in 1993. After a two-year postdoc at Harvard University, she returned to join the MIT faculty in 1995.

At the heart of Hammond’s research is a technique she developed to create thin films that can essentially “shrink-wrap” nanoparticles. By tuning the chemical composition of these films, the particles can be customized to deliver drugs or nucleic acids and to target specific cells in the body, including cancer cells.

To make these films, Hammond begins by layering positively charged polymers onto a negatively charged surface. Then, more layers can be added, alternating positively and negatively charged polymers. Each of these layers may contain drugs or other useful molecules, such as DNA or RNA. Some of these films contain hundreds of layers, others just one, making them useful for a wide range of applications.

“What’s nice about the layer-by-layer process is I can choose a group of degradable polymers that are nicely biocompatible, and I can alternate them with our drug materials. This means that I can build up thin film layers that contain different drugs at different points within the film,” Hammond said. “Then, when the film degrades, it can release those drugs in reverse order. This is enabling us to create complex, multidrug films, using a simple water-based technique.”

Hammond described how these layer-by-layer films can be used to promote bone growth, in an application that could help people born with congenital bone defects or people who experience traumatic injuries.

For that use, her lab has created films with layers of two proteins. One of these, BMP-2, is a protein that interacts with adult stem cells and induces them to differentiate into bone cells, generating new bone. The second is a growth factor called VEGF, which stimulates the growth of new blood vessels that help bone to regenerate. These layers are applied to a very thin tissue scaffold that can be implanted at the injury site.

Hammond and her students designed the coating so that once implanted, it would release VEGF early, over a week or so, and continue releasing BMP-2 for up to 40 days. In a study of mice, they found that this tissue scaffold stimulated the growth of new bone that was nearly indistinguishable from natural bone.

Targeting cancer

As a member of MIT’s Koch Institute for Integrative Cancer Research, Hammond has also developed layer-by-layer coatings that can improve the performance of nanoparticles used for cancer drug delivery, such as liposomes or nanoparticles made from a polymer called PLGA.

“We have a broad range of drug carriers that we can wrap this way. I think of them like a gobstopper, where there are all those different layers of candy and they dissolve one at a time,” Hammond said.

Using this approach, Hammond has created particles that can deliver a one-two punch to cancer cells. First, the particles release a dose of a nucleic acid such as short interfering RNA (siRNA), which can turn off a cancerous gene, or microRNA, which can activate tumor suppressor genes. Then, the particles release a chemotherapy drug such as cisplatin, to which the cells are now more vulnerable.

The particles also include a negatively charged outer “stealth layer” that protects them from being broken down in the bloodstream before they can reach their targets. This outer layer can also be modified to help the particles get taken up by cancer cells, by incorporating molecules that bind to proteins that are abundant on tumor cells.

In more recent work, Hammond has begun developing nanoparticles that can target ovarian cancer and help prevent recurrence of the disease after chemotherapy. In about 70 percent of ovarian cancer patients, the first round of treatment is highly effective, but tumors recur in about 85 percent of those cases, and these new tumors are usually highly drug resistant.

By altering the type of coating applied to drug-delivering nanoparticles, Hammond has found that the particles can be designed to either get inside tumor cells or stick to their surfaces. Using particles that stick to the cells, she has designed a treatment that could help to jumpstart a patient’s immune response to any recurrent tumor cells.

“With ovarian cancer, very few immune cells exist in that space, and because they don’t have a lot of immune cells present, it’s very difficult to rev up an immune response,” she said. “However, if we can deliver a molecule to neighboring cells, those few that are present, and get them revved up, then we might be able to do something.”

To that end, she designed nanoparticles that deliver IL-12, a cytokine that stimulates nearby T cells to spring into action and begin attacking tumor cells. In a study of mice, she found that this treatment induced a long-term memory T-cell response that prevented recurrence of ovarian cancer.

Hammond closed her lecture by describing the impact that the Institute has had on her throughout her career.

“It’s been a transformative experience,” she said. “I really think of this place as special because it brings people together and enables us to do things together that we couldn’t do alone. And it is that support we get from our friends, our colleagues, and our students that really makes things possible.”

© Photo: Jake Belcher

Many vaccines, including vaccines for hepatitis B and whooping cough, consist of fragments of viral or bacterial proteins. These vaccines often include other molecules called adjuvants, which help to boost the immune system’s response to the protein.

Most of these adjuvants consist of aluminum salts or other molecules that provoke a nonspecific immune response. A team of MIT researchers has now shown that a type of nanoparticle called a metal organic framework (MOF) can also provoke a strong immune response, by activating the innate immune system — the body’s first line of defense against any pathogen — through cell proteins called toll-like receptors.

In a study of mice, the researchers showed that this MOF could successfully encapsulate and deliver part of the SARS-CoV-2 spike protein, while also acting as an adjuvant once the MOF is broken down inside cells.

While more work would be needed to adapt these particles for use as vaccines, the study demonstrates that this type of structure can be useful for generating a strong immune response, the researchers say.

“Understanding how the drug delivery vehicle can enhance an adjuvant immune response is something that could be very helpful in designing new vaccines,” says Ana Jaklenec, a principal investigator at MIT’s Koch Institute for Integrative Cancer Research and one of the senior authors of the new study.

Robert Langer, an MIT Institute Professor and member of the Koch Institute, and Dan Barouch, director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center and a professor at Harvard Medical School, are also senior authors of the paper, which appears today in Science Advances. The paper’s lead author is former MIT postdoc and Ibn Khaldun Fellow Shahad Alsaiari.

Immune activation

In this study, the researchers focused on a MOF called ZIF-8, which consists of a lattice of tetrahedral units made up of a zinc ion attached to four molecules of imidazole, an organic compound. Previous work has shown that ZIF-8 can significantly boost immune responses, but it wasn’t known exactly how this particle activates the immune system.

To try to figure that out, the MIT team created an experimental vaccine consisting of the SARS-CoV-2 receptor-binding protein (RBD) embedded within ZIF-8 particles. These particles are between 100 and 200 nanometers in diameter, a size that allows them to get into the body’s lymph nodes directly or through immune cells such as macrophages.

Once the particles enter the cells, the MOFs are broken down, releasing the viral proteins. The researchers found that the imidazole components then activate toll-like receptors (TLRs), which help to stimulate the innate immune response.

“This process is analogous to establishing a covert operative team at the molecular level to transport essential elements of the Covid-19 virus to the body’s immune system, where they can activate specific immune responses to boost vaccine efficacy,” Alsaiari says.

RNA sequencing of cells from the lymph nodes showed that mice vaccinated with ZIF-8 particles carrying the viral protein strongly activated a TLR pathway known as TLR-7, which led to greater production of cytokines and other molecules involved in inflammation.

Mice vaccinated with these particles generated a much stronger response to the viral protein than mice that received the protein on its own.

“Not only are we delivering the protein in a more controlled way through a nanoparticle, but the compositional structure of this particle is also acting as an adjuvant,” Jaklenec says. “We were able to achieve very specific responses to the Covid protein, and with a dose-sparing effect compared to using the protein by itself to vaccinate.”

Vaccine access

While this study and others have demonstrated ZIF-8’s immunogenic ability, more work needs to be done to evaluate the particles’ safety and potential to be scaled up for large-scale manufacturing. If ZIF-8 is not developed as a vaccine carrier, the findings from the study should help to guide researchers in developing similar nanoparticles that could be used to deliver subunit vaccines, Jaklenec says.

“Most subunit vaccines usually have two separate components: an antigen and an adjuvant,” Jaklenec says. “Designing new vaccines that utilize nanoparticles with specific chemical moieties which not only aid in antigen delivery but can also activate particular immune pathways have the potential to enhance vaccine potency.”

One advantage to developing a subunit vaccine for Covid-19 is that such vaccines are usually easier and cheaper to manufacture than mRNA vaccines, which could make it easier to distribute them around the world, the researchers say.

“Subunit vaccines have been around for a long time, and they tend to be cheaper to produce, so that opens up more access to vaccines, especially in times of pandemic,” Jaklenec says.

The research was funded by Ibn Khaldun Fellowships for Saudi Arabian Women and in part by the Koch Institute Support (core) Grant from the U.S. National Cancer Institute.

© Image: Courtesy of the researchers

A team of MIT researchers will lead a $65.67 million effort, awarded by the U.S. Advanced Research Projects Agency for Health (ARPA-H), to develop ingestible devices that may one day be used to treat diabetes, obesity, and other conditions through oral delivery of mRNA. Such devices could potentially be deployed for needle-free delivery of mRNA vaccines as well.

The five-year project also aims to develop electroceuticals, a new form of ingestible therapies based on electrical stimulation of the body’s own hormones and neural signaling. If successful, this approach could lead to new treatments for a variety of metabolic disorders.

“We know that the oral route is generally the preferred route of administration for both patients and health care providers,” says Giovanni Traverso, an associate professor of mechanical engineering at MIT and a gastroenterologist at Brigham and Women’s Hospital. “Our primary focus is on disorders of metabolism because they affect a lot of people, but the platforms we’re developing could be applied very broadly.”

Traverso is the principal investigator for the project, which also includes Robert Langer, MIT Institute Professor, and Anantha Chandrakasan, dean of the MIT School of Engineering and the Vannevar Bush Professor of Electrical Engineering and Computer Science. As part of the project, the MIT team will collaborate with investigators from Brigham and Women’s Hospital, New York University, and the University of Colorado School of Medicine.

Over the past several years, Traverso’s and Langer’s labs have designed many types of ingestible devices that can deliver drugs to the GI tract. This approach could be especially useful for protein drugs and nucleic acids, which typically can’t be given orally because they break down in the acidic environment of the digestive tract.

Messenger RNA has already proven useful as a vaccine, directing cells to produce fragments of viral proteins that trigger an immune response. Delivering mRNA to cells also holds potential to stimulate production of therapeutic molecules to treat a variety of diseases. In this project, the researchers plan to focus on metabolic diseases such as diabetes.

“What mRNA can do is enable the potential for dosing therapies that are very difficult to dose today, or provide longer-term coverage by essentially creating an internal factory that produces a therapy for a prolonged period,” Traverso says.

In the mRNA portion of the project, the research team intends to identify lipid and polymer nanoparticle formulations that can most effectively deliver mRNA to cells, using machine learning to help identify the best candidates. They will also develop and test ingestible devices to carry the mRNA-nanoparticle payload, with the goal of running a clinical trial in the final year of the five-year project.

The work will build on research that Traverso’s lab has already begun. In 2022, Traverso and his colleagues reported that they could deliver mRNA in capsules that inject mRNA-nanoparticle complexes into the lining of the stomach.

The other branch of the project will focus on ingestible devices that can deliver a small electrical current to the lining of the stomach. In a study published last year, Traverso’s lab demonstrated this approach for the first time, using a capsule coated with electrodes that apply an electrical current to cells of the stomach. In animal studies, they found that this stimulation boosted production of ghrelin, a hormone that stimulates appetite.

Traverso envisions that this type of treatment could potentially replace or complement some of the existing drugs used to prevent nausea and stimulate appetite in people with anorexia or cachexia (loss of body mass that can occur in patients with cancer or other chronic diseases). The researchers also hope to develop ways to stimulate production of GLP-1, a hormone that is used to help manage diabetes and promote weight loss.

“What this approach starts to do is potentially maximize our ability to treat disease without administering a new drug, but instead by simply modulating the body’s own systems through electrical stimulation,” Traverso says.

At MIT, Langer will help to develop nanoparticles for mRNA delivery, and Chandrakasan will work on ways to reduce energy consumption and miniaturize the electronic functions of the capsules, including secure communication, stimulation, and power generation.

The Brigham and Women’s Hospital’s portion of the project will be co-led by Traverso, Ameya Kirtane, Jason Li, and Peter Chai, who will amplify efforts on the formulation and stabilization of the mRNA nanoparticles, engineering of the ingestible devices, and running of clinical trials. At NYU, the effort will be led by assistant professor of bioengineering Khalil Ramadi SM ’16, PhD ’19, focusing on biological characterization of the effects of electrical stimulation. Researchers at the University of Colorado, led by Matthew Wynia and Eric G. Campbell of the CU Center for Bioethics and Humanities, will focus on exploring the ethical dimensions and public perceptions of these types of biomedical interventions.

“We felt like we had an opportunity here not only to do fundamental engineering science and early-stage clinical trials, but also to start to understand the data behind some of the ethical implications and public perceptions of these technologies through this broad collaboration,” Traverso says.

The project described here is supported by ARPA-H under award number D24AC00040-00. The content of this announcement does not necessarily represent the official views of the Advanced Research Projects Agency for Health.

© Image: Courtesy of MechE

Using a virus-like delivery particle made from DNA, researchers from MIT and the Ragon Institute of MGH, MIT, and Harvard have created a vaccine that can induce a strong antibody response against SARS-CoV-2.

The vaccine, which has been tested in mice, consists of a DNA scaffold that carries many copies of a viral antigen. This type of vaccine, known as a particulate vaccine, mimics the structure of a virus. Most previous work on particulate vaccines has relied on protein scaffolds, but the proteins used in those vaccines tend to generate an unnecessary immune response that can distract the immune system from the target.

In the mouse study, the researchers found that the DNA scaffold does not induce an immune response, allowing the immune system to focus its antibody response on the target antigen.

“DNA, we found in this work, does not elicit antibodies that may distract away from the protein of interest,” says Mark Bathe, an MIT professor of biological engineering. “What you can imagine is that your B cells and immune system are being fully trained by that target antigen, and that’s what you want — for your immune system to be laser-focused on the antigen of interest.”

This approach, which strongly stimulates B cells (the cells that produce antibodies), could make it easier to develop vaccines against viruses that have been difficult to target, including HIV and influenza, as well as SARS-CoV-2, the researchers say. Unlike T cells, which are stimulated by other types of vaccines, these B cells can persist for decades, offering long-term protection.

“We’re interested in exploring whether we can teach the immune system to deliver higher levels of immunity against pathogens that resist conventional vaccine approaches, like flu, HIV, and SARS-CoV-2,” says Daniel Lingwood, an associate professor at Harvard Medical School and a principal investigator at the Ragon Institute. “This idea of decoupling the response against the target antigen from the platform itself is a potentially powerful immunological trick that one can now bring to bear to help those immunological targeting decisions move in a direction that is more focused.”

Bathe, Lingwood, and Aaron Schmidt, an associate professor at Harvard Medical School and principal investigator at the Ragon Institute, are the senior authors of the paper, which appears today in Nature Communications. The paper’s lead authors are Eike-Christian Wamhoff, a former MIT postdoc; Larance Ronsard, a Ragon Institute postdoc; Jared Feldman, a former Harvard University graduate student; Grant Knappe, an MIT graduate student; and Blake Hauser, a former Harvard graduate student. 

Mimicking viruses

Particulate vaccines usually consist of a protein nanoparticle, similar in structure to a virus, that can carry many copies of a viral antigen. This high density of antigens can lead to a stronger immune response than traditional vaccines because the body sees it as similar to an actual virus. Particulate vaccines have been developed for a handful of pathogens, including hepatitis B and human papillomavirus, and a particulate vaccine for SARS-CoV-2 has been approved for use in South Korea.

These vaccines are especially good at activating B cells, which produce antibodies specific to the vaccine antigen.

“Particulate vaccines are of great interest for many in immunology because they give you robust humoral immunity, which is antibody-based immunity, which is differentiated from the T-cell-based immunity that the mRNA vaccines seem to elicit more strongly,” Bathe says.

A potential drawback to this kind of vaccine, however, is that the proteins used for the scaffold often stimulate the body to produce antibodies targeting the scaffold. This can distract the immune system and prevent it from launching as robust a response as one would like, Bathe says.

“To neutralize the SARS-CoV-2 virus, you want to have a vaccine that generates antibodies toward the receptor binding domain portion of the virus’ spike protein,” he says. “When you display that on a protein-based particle, what happens is your immune system recognizes not only that receptor binding domain protein, but all the other proteins that are irrelevant to the immune response you’re trying to elicit.”

Another potential drawback is that if the same person receives more than one vaccine carried by the same protein scaffold, for example, SARS-CoV-2 and then influenza, their immune system would likely respond right away to the protein scaffold, having already been primed to react to it. This could weaken the immune response to the antigen carried by the second vaccine.

“If you want to apply that protein-based particle to immunize against a different virus like influenza, then your immune system can be addicted to the underlying protein scaffold that it’s already seen and developed an immune response toward,” Bathe says. “That can hypothetically diminish the quality of your antibody response for the actual antigen of interest.”

As an alternative, Bathe’s lab has been developing scaffolds made using DNA origami, a method that offers precise control over the structure of synthetic DNA and allows researchers to attach a variety of molecules, such as viral antigens, at specific locations.

In a 2020 study, Bathe and Darrell Irvine, an MIT professor of biological engineering and of materials science and engineering, showed that a DNA scaffold carrying 30 copies of an HIV antigen could generate a strong antibody response in B cells grown in the lab. This type of structure is optimal for activating B cells because it closely mimics the structure of nano-sized viruses, which display many copies of viral proteins in their surfaces.

“This approach builds off of a fundamental principle in B-cell antigen recognition, which is that if you have an arrayed display of the antigen, that promotes B-cell responses and gives better quantity and quality of antibody output,” Lingwood says.

“Immunologically silent”

In the new study, the researchers swapped in an antigen consisting of the receptor binding protein of the spike protein from the original strain of SARS-CoV-2. When they gave the vaccine to mice, they found that the mice generated high levels of antibodies to the spike protein but did not generate any to the DNA scaffold.

In contrast, a vaccine based on a scaffold protein called ferritin, coated with SARS-CoV-2 antigens, generated many antibodies against ferritin as well as SARS-CoV-2.

“The DNA nanoparticle itself is immunogenically silent,” Lingwood says. “If you use a protein-based platform, you get equally high titer antibody responses to the platform and to the antigen of interest, and that can complicate repeated usage of that platform because you’ll develop high affinity immune memory against it.”

Reducing these off-target effects could also help scientists reach the goal of developing a vaccine that would induce broadly neutralizing antibodies to any variant of SARS-CoV-2, or even to all sarbecoviruses, the subgenus of virus that includes SARS-CoV-2 as well as the viruses that cause SARS and MERS.

To that end, the researchers are now exploring whether a DNA scaffold with many different viral antigens attached could induce broadly neutralizing antibodies against SARS-CoV-2 and related viruses. 

The research was primarily funded by the National Institutes of Health, the National Science Foundation, and the Fast Grants program.

© Credit: The Bathe Lab

When Paula Hammond first arrived on MIT’s campus as a first-year student in the early 1980s, she wasn’t sure if she belonged. In fact, as she told an MIT audience yesterday, she felt like “an imposter.”

However, that feeling didn’t last long, as Hammond began to find support among her fellow students and MIT’s faculty. “Community was really important for me, to feel that I belonged, to feel that I had a place here, and I found people who were willing to embrace me and support me,” she said.

Hammond, a world-renowned chemical engineer who has spent most of her academic career at MIT, made her remarks during the 2023-24 James R. Killian Jr. Faculty Achievement Award lecture.

Established in 1971 to honor MIT’s 10th president, James Killian, the Killian Award recognizes extraordinary professional achievements by an MIT faculty member. Hammond was chosen for this year’s award “not only for her tremendous professional achievements and contributions, but also for her genuine warmth and humanity, her thoughtfulness and effective leadership, and her empathy and ethics,” according to the award citation.

“Professor Hammond is a pioneer in nanotechnology research. With a program that extends from basic science to translational research in medicine and energy, she has introduced new approaches for the design and development of complex drug delivery systems for cancer treatment and noninvasive imaging,” said Mary Fuller, chair of MIT’s faculty and a professor of literature, who presented the award. “As her colleagues, we are delighted to celebrate her career today.”

In January, Hammond began serving as MIT’s vice provost for faculty. Before that, she chaired the Department of Chemical Engineering for eight years, and she was named an Institute Professor in 2021.

A versatile technique

Hammond, who grew up in Detroit, credits her parents with instilling a love of science. Her father was one of very few Black PhDs in biochemistry at the time, while her mother earned a master’s degree in nursing from Howard University and founded the nursing school at Wayne County Community College. “That provided a huge amount of opportunity for women in the area of Detroit, including women of color,” Hammond noted.

After earning her bachelor’s degree from MIT in 1984, Hammond worked as an engineer before returning to the Institute as a graduate student, earning her PhD in 1993. After a two-year postdoc at Harvard University, she returned to join the MIT faculty in 1995.

At the heart of Hammond’s research is a technique she developed to create thin films that can essentially “shrink-wrap” nanoparticles. By tuning the chemical composition of these films, the particles can be customized to deliver drugs or nucleic acids and to target specific cells in the body, including cancer cells.

To make these films, Hammond begins by layering positively charged polymers onto a negatively charged surface. Then, more layers can be added, alternating positively and negatively charged polymers. Each of these layers may contain drugs or other useful molecules, such as DNA or RNA. Some of these films contain hundreds of layers, others just one, making them useful for a wide range of applications.

“What’s nice about the layer-by-layer process is I can choose a group of degradable polymers that are nicely biocompatible, and I can alternate them with our drug materials. This means that I can build up thin film layers that contain different drugs at different points within the film,” Hammond said. “Then, when the film degrades, it can release those drugs in reverse order. This is enabling us to create complex, multidrug films, using a simple water-based technique.”

Hammond described how these layer-by-layer films can be used to promote bone growth, in an application that could help people born with congenital bone defects or people who experience traumatic injuries.

For that use, her lab has created films with layers of two proteins. One of these, BMP-2, is a protein that interacts with adult stem cells and induces them to differentiate into bone cells, generating new bone. The second is a growth factor called VEGF, which stimulates the growth of new blood vessels that help bone to regenerate. These layers are applied to a very thin tissue scaffold that can be implanted at the injury site.

Hammond and her students designed the coating so that once implanted, it would release VEGF early, over a week or so, and continue releasing BMP-2 for up to 40 days. In a study of mice, they found that this tissue scaffold stimulated the growth of new bone that was nearly indistinguishable from natural bone.

Targeting cancer

As a member of MIT’s Koch Institute for Integrative Cancer Research, Hammond has also developed layer-by-layer coatings that can improve the performance of nanoparticles used for cancer drug delivery, such as liposomes or nanoparticles made from a polymer called PLGA.

“We have a broad range of drug carriers that we can wrap this way. I think of them like a gobstopper, where there are all those different layers of candy and they dissolve one at a time,” Hammond said.

Using this approach, Hammond has created particles that can deliver a one-two punch to cancer cells. First, the particles release a dose of a nucleic acid such as short interfering RNA (siRNA), which can turn off a cancerous gene, or microRNA, which can activate tumor suppressor genes. Then, the particles release a chemotherapy drug such as cisplatin, to which the cells are now more vulnerable.

The particles also include a negatively charged outer “stealth layer” that protects them from being broken down in the bloodstream before they can reach their targets. This outer layer can also be modified to help the particles get taken up by cancer cells, by incorporating molecules that bind to proteins that are abundant on tumor cells.

In more recent work, Hammond has begun developing nanoparticles that can target ovarian cancer and help prevent recurrence of the disease after chemotherapy. In about 70 percent of ovarian cancer patients, the first round of treatment is highly effective, but tumors recur in about 85 percent of those cases, and these new tumors are usually highly drug resistant.

By altering the type of coating applied to drug-delivering nanoparticles, Hammond has found that the particles can be designed to either get inside tumor cells or stick to their surfaces. Using particles that stick to the cells, she has designed a treatment that could help to jumpstart a patient’s immune response to any recurrent tumor cells.

“With ovarian cancer, very few immune cells exist in that space, and because they don’t have a lot of immune cells present, it’s very difficult to rev up an immune response,” she said. “However, if we can deliver a molecule to neighboring cells, those few that are present, and get them revved up, then we might be able to do something.”

To that end, she designed nanoparticles that deliver IL-12, a cytokine that stimulates nearby T cells to spring into action and begin attacking tumor cells. In a study of mice, she found that this treatment induced a long-term memory T-cell response that prevented recurrence of ovarian cancer.

Hammond closed her lecture by describing the impact that the Institute has had on her throughout her career.

“It’s been a transformative experience,” she said. “I really think of this place as special because it brings people together and enables us to do things together that we couldn’t do alone. And it is that support we get from our friends, our colleagues, and our students that really makes things possible.”

© Photo: Jake Belcher

Many vaccines, including vaccines for hepatitis B and whooping cough, consist of fragments of viral or bacterial proteins. These vaccines often include other molecules called adjuvants, which help to boost the immune system’s response to the protein.

Most of these adjuvants consist of aluminum salts or other molecules that provoke a nonspecific immune response. A team of MIT researchers has now shown that a type of nanoparticle called a metal organic framework (MOF) can also provoke a strong immune response, by activating the innate immune system — the body’s first line of defense against any pathogen — through cell proteins called toll-like receptors.

In a study of mice, the researchers showed that this MOF could successfully encapsulate and deliver part of the SARS-CoV-2 spike protein, while also acting as an adjuvant once the MOF is broken down inside cells.

While more work would be needed to adapt these particles for use as vaccines, the study demonstrates that this type of structure can be useful for generating a strong immune response, the researchers say.

“Understanding how the drug delivery vehicle can enhance an adjuvant immune response is something that could be very helpful in designing new vaccines,” says Ana Jaklenec, a principal investigator at MIT’s Koch Institute for Integrative Cancer Research and one of the senior authors of the new study.

Robert Langer, an MIT Institute Professor and member of the Koch Institute, and Dan Barouch, director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center and a professor at Harvard Medical School, are also senior authors of the paper, which appears today in Science Advances. The paper’s lead author is former MIT postdoc and Ibn Khaldun Fellow Shahad Alsaiari.

Immune activation

In this study, the researchers focused on a MOF called ZIF-8, which consists of a lattice of tetrahedral units made up of a zinc ion attached to four molecules of imidazole, an organic compound. Previous work has shown that ZIF-8 can significantly boost immune responses, but it wasn’t known exactly how this particle activates the immune system.

To try to figure that out, the MIT team created an experimental vaccine consisting of the SARS-CoV-2 receptor-binding protein (RBD) embedded within ZIF-8 particles. These particles are between 100 and 200 nanometers in diameter, a size that allows them to get into the body’s lymph nodes directly or through immune cells such as macrophages.

Once the particles enter the cells, the MOFs are broken down, releasing the viral proteins. The researchers found that the imidazole components then activate toll-like receptors (TLRs), which help to stimulate the innate immune response.

“This process is analogous to establishing a covert operative team at the molecular level to transport essential elements of the Covid-19 virus to the body’s immune system, where they can activate specific immune responses to boost vaccine efficacy,” Alsaiari says.

RNA sequencing of cells from the lymph nodes showed that mice vaccinated with ZIF-8 particles carrying the viral protein strongly activated a TLR pathway known as TLR-7, which led to greater production of cytokines and other molecules involved in inflammation.

Mice vaccinated with these particles generated a much stronger response to the viral protein than mice that received the protein on its own.

“Not only are we delivering the protein in a more controlled way through a nanoparticle, but the compositional structure of this particle is also acting as an adjuvant,” Jaklenec says. “We were able to achieve very specific responses to the Covid protein, and with a dose-sparing effect compared to using the protein by itself to vaccinate.”

Vaccine access

While this study and others have demonstrated ZIF-8’s immunogenic ability, more work needs to be done to evaluate the particles’ safety and potential to be scaled up for large-scale manufacturing. If ZIF-8 is not developed as a vaccine carrier, the findings from the study should help to guide researchers in developing similar nanoparticles that could be used to deliver subunit vaccines, Jaklenec says.

“Most subunit vaccines usually have two separate components: an antigen and an adjuvant,” Jaklenec says. “Designing new vaccines that utilize nanoparticles with specific chemical moieties which not only aid in antigen delivery but can also activate particular immune pathways have the potential to enhance vaccine potency.”

One advantage to developing a subunit vaccine for Covid-19 is that such vaccines are usually easier and cheaper to manufacture than mRNA vaccines, which could make it easier to distribute them around the world, the researchers say.

“Subunit vaccines have been around for a long time, and they tend to be cheaper to produce, so that opens up more access to vaccines, especially in times of pandemic,” Jaklenec says.

The research was funded by Ibn Khaldun Fellowships for Saudi Arabian Women and in part by the Koch Institute Support (core) Grant from the U.S. National Cancer Institute.

© Image: Courtesy of the researchers

A team of MIT researchers will lead a $65.67 million effort, awarded by the U.S. Advanced Research Projects Agency for Health (ARPA-H), to develop ingestible devices that may one day be used to treat diabetes, obesity, and other conditions through oral delivery of mRNA. Such devices could potentially be deployed for needle-free delivery of mRNA vaccines as well.

The five-year project also aims to develop electroceuticals, a new form of ingestible therapies based on electrical stimulation of the body’s own hormones and neural signaling. If successful, this approach could lead to new treatments for a variety of metabolic disorders.

“We know that the oral route is generally the preferred route of administration for both patients and health care providers,” says Giovanni Traverso, an associate professor of mechanical engineering at MIT and a gastroenterologist at Brigham and Women’s Hospital. “Our primary focus is on disorders of metabolism because they affect a lot of people, but the platforms we’re developing could be applied very broadly.”

Traverso is the principal investigator for the project, which also includes Robert Langer, MIT Institute Professor, and Anantha Chandrakasan, dean of the MIT School of Engineering and the Vannevar Bush Professor of Electrical Engineering and Computer Science. As part of the project, the MIT team will collaborate with investigators from Brigham and Women’s Hospital, New York University, and the University of Colorado School of Medicine.

Over the past several years, Traverso’s and Langer’s labs have designed many types of ingestible devices that can deliver drugs to the GI tract. This approach could be especially useful for protein drugs and nucleic acids, which typically can’t be given orally because they break down in the acidic environment of the digestive tract.

Messenger RNA has already proven useful as a vaccine, directing cells to produce fragments of viral proteins that trigger an immune response. Delivering mRNA to cells also holds potential to stimulate production of therapeutic molecules to treat a variety of diseases. In this project, the researchers plan to focus on metabolic diseases such as diabetes.

“What mRNA can do is enable the potential for dosing therapies that are very difficult to dose today, or provide longer-term coverage by essentially creating an internal factory that produces a therapy for a prolonged period,” Traverso says.

In the mRNA portion of the project, the research team intends to identify lipid and polymer nanoparticle formulations that can most effectively deliver mRNA to cells, using machine learning to help identify the best candidates. They will also develop and test ingestible devices to carry the mRNA-nanoparticle payload, with the goal of running a clinical trial in the final year of the five-year project.

The work will build on research that Traverso’s lab has already begun. In 2022, Traverso and his colleagues reported that they could deliver mRNA in capsules that inject mRNA-nanoparticle complexes into the lining of the stomach.

The other branch of the project will focus on ingestible devices that can deliver a small electrical current to the lining of the stomach. In a study published last year, Traverso’s lab demonstrated this approach for the first time, using a capsule coated with electrodes that apply an electrical current to cells of the stomach. In animal studies, they found that this stimulation boosted production of ghrelin, a hormone that stimulates appetite.

Traverso envisions that this type of treatment could potentially replace or complement some of the existing drugs used to prevent nausea and stimulate appetite in people with anorexia or cachexia (loss of body mass that can occur in patients with cancer or other chronic diseases). The researchers also hope to develop ways to stimulate production of GLP-1, a hormone that is used to help manage diabetes and promote weight loss.

“What this approach starts to do is potentially maximize our ability to treat disease without administering a new drug, but instead by simply modulating the body’s own systems through electrical stimulation,” Traverso says.

At MIT, Langer will help to develop nanoparticles for mRNA delivery, and Chandrakasan will work on ways to reduce energy consumption and miniaturize the electronic functions of the capsules, including secure communication, stimulation, and power generation.

The Brigham and Women’s Hospital’s portion of the project will be co-led by Traverso, Ameya Kirtane, Jason Li, and Peter Chai, who will amplify efforts on the formulation and stabilization of the mRNA nanoparticles, engineering of the ingestible devices, and running of clinical trials. At NYU, the effort will be led by assistant professor of bioengineering Khalil Ramadi SM ’16, PhD ’19, focusing on biological characterization of the effects of electrical stimulation. Researchers at the University of Colorado, led by Matthew Wynia and Eric G. Campbell of the CU Center for Bioethics and Humanities, will focus on exploring the ethical dimensions and public perceptions of these types of biomedical interventions.

“We felt like we had an opportunity here not only to do fundamental engineering science and early-stage clinical trials, but also to start to understand the data behind some of the ethical implications and public perceptions of these technologies through this broad collaboration,” Traverso says.

The project described here is supported by ARPA-H under award number D24AC00040-00. The content of this announcement does not necessarily represent the official views of the Advanced Research Projects Agency for Health.

© Image: Courtesy of MechE

Using a virus-like delivery particle made from DNA, researchers from MIT and the Ragon Institute of MGH, MIT, and Harvard have created a vaccine that can induce a strong antibody response against SARS-CoV-2.

The vaccine, which has been tested in mice, consists of a DNA scaffold that carries many copies of a viral antigen. This type of vaccine, known as a particulate vaccine, mimics the structure of a virus. Most previous work on particulate vaccines has relied on protein scaffolds, but the proteins used in those vaccines tend to generate an unnecessary immune response that can distract the immune system from the target.

In the mouse study, the researchers found that the DNA scaffold does not induce an immune response, allowing the immune system to focus its antibody response on the target antigen.

“DNA, we found in this work, does not elicit antibodies that may distract away from the protein of interest,” says Mark Bathe, an MIT professor of biological engineering. “What you can imagine is that your B cells and immune system are being fully trained by that target antigen, and that’s what you want — for your immune system to be laser-focused on the antigen of interest.”

This approach, which strongly stimulates B cells (the cells that produce antibodies), could make it easier to develop vaccines against viruses that have been difficult to target, including HIV and influenza, as well as SARS-CoV-2, the researchers say. Unlike T cells, which are stimulated by other types of vaccines, these B cells can persist for decades, offering long-term protection.

“We’re interested in exploring whether we can teach the immune system to deliver higher levels of immunity against pathogens that resist conventional vaccine approaches, like flu, HIV, and SARS-CoV-2,” says Daniel Lingwood, an associate professor at Harvard Medical School and a principal investigator at the Ragon Institute. “This idea of decoupling the response against the target antigen from the platform itself is a potentially powerful immunological trick that one can now bring to bear to help those immunological targeting decisions move in a direction that is more focused.”

Bathe, Lingwood, and Aaron Schmidt, an associate professor at Harvard Medical School and principal investigator at the Ragon Institute, are the senior authors of the paper, which appears today in Nature Communications. The paper’s lead authors are Eike-Christian Wamhoff, a former MIT postdoc; Larance Ronsard, a Ragon Institute postdoc; Jared Feldman, a former Harvard University graduate student; Grant Knappe, an MIT graduate student; and Blake Hauser, a former Harvard graduate student. 

Mimicking viruses

Particulate vaccines usually consist of a protein nanoparticle, similar in structure to a virus, that can carry many copies of a viral antigen. This high density of antigens can lead to a stronger immune response than traditional vaccines because the body sees it as similar to an actual virus. Particulate vaccines have been developed for a handful of pathogens, including hepatitis B and human papillomavirus, and a particulate vaccine for SARS-CoV-2 has been approved for use in South Korea.

These vaccines are especially good at activating B cells, which produce antibodies specific to the vaccine antigen.

“Particulate vaccines are of great interest for many in immunology because they give you robust humoral immunity, which is antibody-based immunity, which is differentiated from the T-cell-based immunity that the mRNA vaccines seem to elicit more strongly,” Bathe says.

A potential drawback to this kind of vaccine, however, is that the proteins used for the scaffold often stimulate the body to produce antibodies targeting the scaffold. This can distract the immune system and prevent it from launching as robust a response as one would like, Bathe says.

“To neutralize the SARS-CoV-2 virus, you want to have a vaccine that generates antibodies toward the receptor binding domain portion of the virus’ spike protein,” he says. “When you display that on a protein-based particle, what happens is your immune system recognizes not only that receptor binding domain protein, but all the other proteins that are irrelevant to the immune response you’re trying to elicit.”

Another potential drawback is that if the same person receives more than one vaccine carried by the same protein scaffold, for example, SARS-CoV-2 and then influenza, their immune system would likely respond right away to the protein scaffold, having already been primed to react to it. This could weaken the immune response to the antigen carried by the second vaccine.

“If you want to apply that protein-based particle to immunize against a different virus like influenza, then your immune system can be addicted to the underlying protein scaffold that it’s already seen and developed an immune response toward,” Bathe says. “That can hypothetically diminish the quality of your antibody response for the actual antigen of interest.”

As an alternative, Bathe’s lab has been developing scaffolds made using DNA origami, a method that offers precise control over the structure of synthetic DNA and allows researchers to attach a variety of molecules, such as viral antigens, at specific locations.

In a 2020 study, Bathe and Darrell Irvine, an MIT professor of biological engineering and of materials science and engineering, showed that a DNA scaffold carrying 30 copies of an HIV antigen could generate a strong antibody response in B cells grown in the lab. This type of structure is optimal for activating B cells because it closely mimics the structure of nano-sized viruses, which display many copies of viral proteins in their surfaces.

“This approach builds off of a fundamental principle in B-cell antigen recognition, which is that if you have an arrayed display of the antigen, that promotes B-cell responses and gives better quantity and quality of antibody output,” Lingwood says.

“Immunologically silent”

In the new study, the researchers swapped in an antigen consisting of the receptor binding protein of the spike protein from the original strain of SARS-CoV-2. When they gave the vaccine to mice, they found that the mice generated high levels of antibodies to the spike protein but did not generate any to the DNA scaffold.

In contrast, a vaccine based on a scaffold protein called ferritin, coated with SARS-CoV-2 antigens, generated many antibodies against ferritin as well as SARS-CoV-2.

“The DNA nanoparticle itself is immunogenically silent,” Lingwood says. “If you use a protein-based platform, you get equally high titer antibody responses to the platform and to the antigen of interest, and that can complicate repeated usage of that platform because you’ll develop high affinity immune memory against it.”

Reducing these off-target effects could also help scientists reach the goal of developing a vaccine that would induce broadly neutralizing antibodies to any variant of SARS-CoV-2, or even to all sarbecoviruses, the subgenus of virus that includes SARS-CoV-2 as well as the viruses that cause SARS and MERS.

To that end, the researchers are now exploring whether a DNA scaffold with many different viral antigens attached could induce broadly neutralizing antibodies against SARS-CoV-2 and related viruses. 

The research was primarily funded by the National Institutes of Health, the National Science Foundation, and the Fast Grants program.

© Credit: The Bathe Lab

Tumors constantly shed DNA from dying cells, which briefly circulates in the patient’s bloodstream before it is quickly broken down. Many companies have created blood tests that can pick out this tumor DNA, potentially helping doctors diagnose or monitor cancer or choose a treatment.

The amount of tumor DNA circulating at any given time, however, is extremely small, so it has been challenging to develop tests sensitive enough to pick up that tiny signal. A team of researchers from MIT and the Broad Institute of MIT and Harvard has now come up with a way to significantly boost that signal, by temporarily slowing the clearance of tumor DNA circulating in the bloodstream.

The researchers developed two different types of injectable molecules that they call “priming agents,” which can transiently interfere with the body’s ability to remove circulating tumor DNA from the bloodstream. In a study of mice, they showed that these agents could boost DNA levels enough that the percentage of detectable early-stage lung metastases leapt from less than 10 percent to above 75 percent.

This approach could enable not only earlier diagnosis of cancer, but also more sensitive detection of tumor mutations that could be used to guide treatment. It could also help improve detection of cancer recurrence.

“You can give one of these agents an hour before the blood draw, and it makes things visible that previously wouldn’t have been. The implication is that we should be able to give everybody who’s doing liquid biopsies, for any purpose, more molecules to work with,” says Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and of Electrical Engineering and Computer Science at MIT, and a member of MIT’s Koch Institute for Integrative Cancer Research and the Institute for Medical Engineering and Science.

Bhatia is one of the senior authors of the new study, along with J. Christopher Love, the Raymond A. and Helen E. St. Laurent Professor of Chemical Engineering at MIT and a member of the Koch Institute and the Ragon Institute of MGH, MIT, and Harvard and Viktor Adalsteinsson, director of the Gerstner Center for Cancer Diagnostics at the Broad Institute.

Carmen Martin-Alonso PhD ’23, MIT and Broad Institute postdoc Shervin Tabrizi, and Broad Institute scientist Kan Xiong are the lead authors of the paper, which appears today in Science.

Better biopsies

Liquid biopsies, which enable detection of small quantities of DNA in blood samples, are now used in many cancer patients to identify mutations that could help guide treatment. With greater sensitivity, however, these tests could become useful for far more patients. Most efforts to improve the sensitivity of liquid biopsies have focused on developing new sequencing technologies to use after the blood is drawn.

While brainstorming ways to make liquid biopsies more informative, Bhatia, Love, Adalsteinsson, and their trainees came up with the idea of trying to increase the amount of DNA in a patient’s bloodstream before the sample is taken.

“A tumor is always creating new cell-free DNA, and that’s the signal that we’re attempting to detect in the blood draw. Existing liquid biopsy technologies, however, are limited by the amount of material you collect in the tube of blood,” Love says. “Where this work intercedes is thinking about how to inject something beforehand that would help boost or enhance the amount of signal that is available to collect in the same small sample.”

The body uses two primary strategies to remove circulating DNA from the bloodstream. Enzymes called DNases circulate in the blood and break down DNA that they encounter, while immune cells known as macrophages take up cell-free DNA as blood is filtered through the liver.

The researchers decided to target each of these processes separately. To prevent DNases from breaking down DNA, they designed a monoclonal antibody that binds to circulating DNA and protects it from the enzymes.

“Antibodies are well-established biopharmaceutical modalities, and they’re safe in a number of different disease contexts, including cancer and autoimmune treatments,” Love says. “The idea was, could we use this kind of antibody to help shield the DNA temporarily from degradation by the nucleases that are in circulation? And by doing so, we shift the balance to where the tumor is generating DNA slightly faster than is being degraded, increasing the concentration in a blood draw.”

The other priming agent they developed is a nanoparticle designed to block macrophages from taking up cell-free DNA. These cells have a well-known tendency to eat up synthetic nanoparticles.

“DNA is a biological nanoparticle, and it made sense that immune cells in the liver were probably taking this up just like they do synthetic nanoparticles. And if that were the case, which it turned out to be, then we could use a safe dummy nanoparticle to distract those immune cells and leave the circulating DNA alone so that it could be at a higher concentration,” Bhatia says.

Earlier tumor detection

The researchers tested their priming agents in mice that received transplants of cancer cells that tend to form tumors in the lungs. Two weeks after the cells were transplanted, the researchers showed that these priming agents could boost the amount of circulating tumor DNA recovered in a blood sample by up to 60-fold.

Once the blood sample is taken, it can be run through the same kinds of sequencing tests now used on liquid biopsy samples. These tests can pick out tumor DNA, including specific sequences used to determine the type of tumor and potentially what kinds of treatments would work best.

Early detection of cancer is another promising application for these priming agents. The researchers found that when mice were given the nanoparticle priming agent before blood was drawn, it allowed them to detect circulating tumor DNA in blood of 75 percent of the mice with low cancer burden, while none were detectable without this boost.

“One of the greatest hurdles for cancer liquid biopsy testing has been the scarcity of circulating tumor DNA in a blood sample,” Adalsteinsson says. “It’s thus been encouraging to see the magnitude of the effect we’ve been able to achieve so far and to envision what impact this could have for patients.”

After either of the priming agents are injected, it takes an hour or two for the DNA levels to increase in the bloodstream, and then they return to normal within about 24 hours.

“The ability to get peak activity of these agents within a couple of hours, followed by their rapid clearance, means that someone could go into a doctor’s office, receive an agent like this, and then give their blood for the test itself, all within one visit,” Love says. “This feature bodes well for the potential to translate this concept into clinical use.”

The researchers have launched a company called Amplifyer Bio that plans to further develop the technology, in hopes of advancing to clinical trials.

“A tube of blood is a much more accessible diagnostic than colonoscopy screening or even mammography,” Bhatia says. “Ultimately, if these tools really are predictive, then we should be able to get many more patients into the system who could benefit from cancer interception or better therapy.”

The research was funded by the Koch Institute Support (core) Grant from the National Cancer Institute, the Marble Center for Cancer Nanomedicine, the Gerstner Family Foundation, the Ludwig Center at MIT, the Koch Institute Frontier Research Program via the Casey and Family Foundation, and the Bridge Project, a partnership between the Koch Institute and the Dana-Farber/Harvard Cancer Center.

© Image: MIT News; iStock

When Paula Hammond first arrived on MIT’s campus as a first-year student in the early 1980s, she wasn’t sure if she belonged. In fact, as she told an MIT audience yesterday, she felt like “an imposter.”

However, that feeling didn’t last long, as Hammond began to find support among her fellow students and MIT’s faculty. “Community was really important for me, to feel that I belonged, to feel that I had a place here, and I found people who were willing to embrace me and support me,” she said.

Hammond, a world-renowned chemical engineer who has spent most of her academic career at MIT, made her remarks during the 2023-24 James R. Killian Jr. Faculty Achievement Award lecture.

Established in 1971 to honor MIT’s 10th president, James Killian, the Killian Award recognizes extraordinary professional achievements by an MIT faculty member. Hammond was chosen for this year’s award “not only for her tremendous professional achievements and contributions, but also for her genuine warmth and humanity, her thoughtfulness and effective leadership, and her empathy and ethics,” according to the award citation.

“Professor Hammond is a pioneer in nanotechnology research. With a program that extends from basic science to translational research in medicine and energy, she has introduced new approaches for the design and development of complex drug delivery systems for cancer treatment and noninvasive imaging,” said Mary Fuller, chair of MIT’s faculty and a professor of literature, who presented the award. “As her colleagues, we are delighted to celebrate her career today.”

In January, Hammond began serving as MIT’s vice provost for faculty. Before that, she chaired the Department of Chemical Engineering for eight years, and she was named an Institute Professor in 2021.

A versatile technique

Hammond, who grew up in Detroit, credits her parents with instilling a love of science. Her father was one of very few Black PhDs in biochemistry at the time, while her mother earned a master’s degree in nursing from Howard University and founded the nursing school at Wayne County Community College. “That provided a huge amount of opportunity for women in the area of Detroit, including women of color,” Hammond noted.

After earning her bachelor’s degree from MIT in 1984, Hammond worked as an engineer before returning to the Institute as a graduate student, earning her PhD in 1993. After a two-year postdoc at Harvard University, she returned to join the MIT faculty in 1995.

At the heart of Hammond’s research is a technique she developed to create thin films that can essentially “shrink-wrap” nanoparticles. By tuning the chemical composition of these films, the particles can be customized to deliver drugs or nucleic acids and to target specific cells in the body, including cancer cells.

To make these films, Hammond begins by layering positively charged polymers onto a negatively charged surface. Then, more layers can be added, alternating positively and negatively charged polymers. Each of these layers may contain drugs or other useful molecules, such as DNA or RNA. Some of these films contain hundreds of layers, others just one, making them useful for a wide range of applications.

“What’s nice about the layer-by-layer process is I can choose a group of degradable polymers that are nicely biocompatible, and I can alternate them with our drug materials. This means that I can build up thin film layers that contain different drugs at different points within the film,” Hammond said. “Then, when the film degrades, it can release those drugs in reverse order. This is enabling us to create complex, multidrug films, using a simple water-based technique.”

Hammond described how these layer-by-layer films can be used to promote bone growth, in an application that could help people born with congenital bone defects or people who experience traumatic injuries.

For that use, her lab has created films with layers of two proteins. One of these, BMP-2, is a protein that interacts with adult stem cells and induces them to differentiate into bone cells, generating new bone. The second is a growth factor called VEGF, which stimulates the growth of new blood vessels that help bone to regenerate. These layers are applied to a very thin tissue scaffold that can be implanted at the injury site.

Hammond and her students designed the coating so that once implanted, it would release VEGF early, over a week or so, and continue releasing BMP-2 for up to 40 days. In a study of mice, they found that this tissue scaffold stimulated the growth of new bone that was nearly indistinguishable from natural bone.

Targeting cancer

As a member of MIT’s Koch Institute for Integrative Cancer Research, Hammond has also developed layer-by-layer coatings that can improve the performance of nanoparticles used for cancer drug delivery, such as liposomes or nanoparticles made from a polymer called PLGA.

“We have a broad range of drug carriers that we can wrap this way. I think of them like a gobstopper, where there are all those different layers of candy and they dissolve one at a time,” Hammond said.

Using this approach, Hammond has created particles that can deliver a one-two punch to cancer cells. First, the particles release a dose of a nucleic acid such as short interfering RNA (siRNA), which can turn off a cancerous gene, or microRNA, which can activate tumor suppressor genes. Then, the particles release a chemotherapy drug such as cisplatin, to which the cells are now more vulnerable.

The particles also include a negatively charged outer “stealth layer” that protects them from being broken down in the bloodstream before they can reach their targets. This outer layer can also be modified to help the particles get taken up by cancer cells, by incorporating molecules that bind to proteins that are abundant on tumor cells.

In more recent work, Hammond has begun developing nanoparticles that can target ovarian cancer and help prevent recurrence of the disease after chemotherapy. In about 70 percent of ovarian cancer patients, the first round of treatment is highly effective, but tumors recur in about 85 percent of those cases, and these new tumors are usually highly drug resistant.

By altering the type of coating applied to drug-delivering nanoparticles, Hammond has found that the particles can be designed to either get inside tumor cells or stick to their surfaces. Using particles that stick to the cells, she has designed a treatment that could help to jumpstart a patient’s immune response to any recurrent tumor cells.

“With ovarian cancer, very few immune cells exist in that space, and because they don’t have a lot of immune cells present, it’s very difficult to rev up an immune response,” she said. “However, if we can deliver a molecule to neighboring cells, those few that are present, and get them revved up, then we might be able to do something.”

To that end, she designed nanoparticles that deliver IL-12, a cytokine that stimulates nearby T cells to spring into action and begin attacking tumor cells. In a study of mice, she found that this treatment induced a long-term memory T-cell response that prevented recurrence of ovarian cancer.

Hammond closed her lecture by describing the impact that the Institute has had on her throughout her career.

“It’s been a transformative experience,” she said. “I really think of this place as special because it brings people together and enables us to do things together that we couldn’t do alone. And it is that support we get from our friends, our colleagues, and our students that really makes things possible.”

© Photo: Jake Belcher

Many vaccines, including vaccines for hepatitis B and whooping cough, consist of fragments of viral or bacterial proteins. These vaccines often include other molecules called adjuvants, which help to boost the immune system’s response to the protein.

Most of these adjuvants consist of aluminum salts or other molecules that provoke a nonspecific immune response. A team of MIT researchers has now shown that a type of nanoparticle called a metal organic framework (MOF) can also provoke a strong immune response, by activating the innate immune system — the body’s first line of defense against any pathogen — through cell proteins called toll-like receptors.

In a study of mice, the researchers showed that this MOF could successfully encapsulate and deliver part of the SARS-CoV-2 spike protein, while also acting as an adjuvant once the MOF is broken down inside cells.

While more work would be needed to adapt these particles for use as vaccines, the study demonstrates that this type of structure can be useful for generating a strong immune response, the researchers say.

“Understanding how the drug delivery vehicle can enhance an adjuvant immune response is something that could be very helpful in designing new vaccines,” says Ana Jaklenec, a principal investigator at MIT’s Koch Institute for Integrative Cancer Research and one of the senior authors of the new study.

Robert Langer, an MIT Institute Professor and member of the Koch Institute, and Dan Barouch, director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center and a professor at Harvard Medical School, are also senior authors of the paper, which appears today in Science Advances. The paper’s lead author is former MIT postdoc and Ibn Khaldun Fellow Shahad Alsaiari.

Immune activation

In this study, the researchers focused on a MOF called ZIF-8, which consists of a lattice of tetrahedral units made up of a zinc ion attached to four molecules of imidazole, an organic compound. Previous work has shown that ZIF-8 can significantly boost immune responses, but it wasn’t known exactly how this particle activates the immune system.

To try to figure that out, the MIT team created an experimental vaccine consisting of the SARS-CoV-2 receptor-binding protein (RBD) embedded within ZIF-8 particles. These particles are between 100 and 200 nanometers in diameter, a size that allows them to get into the body’s lymph nodes directly or through immune cells such as macrophages.

Once the particles enter the cells, the MOFs are broken down, releasing the viral proteins. The researchers found that the imidazole components then activate toll-like receptors (TLRs), which help to stimulate the innate immune response.

“This process is analogous to establishing a covert operative team at the molecular level to transport essential elements of the Covid-19 virus to the body’s immune system, where they can activate specific immune responses to boost vaccine efficacy,” Alsaiari says.

RNA sequencing of cells from the lymph nodes showed that mice vaccinated with ZIF-8 particles carrying the viral protein strongly activated a TLR pathway known as TLR-7, which led to greater production of cytokines and other molecules involved in inflammation.

Mice vaccinated with these particles generated a much stronger response to the viral protein than mice that received the protein on its own.

“Not only are we delivering the protein in a more controlled way through a nanoparticle, but the compositional structure of this particle is also acting as an adjuvant,” Jaklenec says. “We were able to achieve very specific responses to the Covid protein, and with a dose-sparing effect compared to using the protein by itself to vaccinate.”

Vaccine access

While this study and others have demonstrated ZIF-8’s immunogenic ability, more work needs to be done to evaluate the particles’ safety and potential to be scaled up for large-scale manufacturing. If ZIF-8 is not developed as a vaccine carrier, the findings from the study should help to guide researchers in developing similar nanoparticles that could be used to deliver subunit vaccines, Jaklenec says.

“Most subunit vaccines usually have two separate components: an antigen and an adjuvant,” Jaklenec says. “Designing new vaccines that utilize nanoparticles with specific chemical moieties which not only aid in antigen delivery but can also activate particular immune pathways have the potential to enhance vaccine potency.”

One advantage to developing a subunit vaccine for Covid-19 is that such vaccines are usually easier and cheaper to manufacture than mRNA vaccines, which could make it easier to distribute them around the world, the researchers say.

“Subunit vaccines have been around for a long time, and they tend to be cheaper to produce, so that opens up more access to vaccines, especially in times of pandemic,” Jaklenec says.

The research was funded by Ibn Khaldun Fellowships for Saudi Arabian Women and in part by the Koch Institute Support (core) Grant from the U.S. National Cancer Institute.

© Image: Courtesy of the researchers

A team of MIT researchers will lead a $65.67 million effort, awarded by the U.S. Advanced Research Projects Agency for Health (ARPA-H), to develop ingestible devices that may one day be used to treat diabetes, obesity, and other conditions through oral delivery of mRNA. Such devices could potentially be deployed for needle-free delivery of mRNA vaccines as well.

The five-year project also aims to develop electroceuticals, a new form of ingestible therapies based on electrical stimulation of the body’s own hormones and neural signaling. If successful, this approach could lead to new treatments for a variety of metabolic disorders.

“We know that the oral route is generally the preferred route of administration for both patients and health care providers,” says Giovanni Traverso, an associate professor of mechanical engineering at MIT and a gastroenterologist at Brigham and Women’s Hospital. “Our primary focus is on disorders of metabolism because they affect a lot of people, but the platforms we’re developing could be applied very broadly.”

Traverso is the principal investigator for the project, which also includes Robert Langer, MIT Institute Professor, and Anantha Chandrakasan, dean of the MIT School of Engineering and the Vannevar Bush Professor of Electrical Engineering and Computer Science. As part of the project, the MIT team will collaborate with investigators from Brigham and Women’s Hospital, New York University, and the University of Colorado School of Medicine.

Over the past several years, Traverso’s and Langer’s labs have designed many types of ingestible devices that can deliver drugs to the GI tract. This approach could be especially useful for protein drugs and nucleic acids, which typically can’t be given orally because they break down in the acidic environment of the digestive tract.

Messenger RNA has already proven useful as a vaccine, directing cells to produce fragments of viral proteins that trigger an immune response. Delivering mRNA to cells also holds potential to stimulate production of therapeutic molecules to treat a variety of diseases. In this project, the researchers plan to focus on metabolic diseases such as diabetes.

“What mRNA can do is enable the potential for dosing therapies that are very difficult to dose today, or provide longer-term coverage by essentially creating an internal factory that produces a therapy for a prolonged period,” Traverso says.

In the mRNA portion of the project, the research team intends to identify lipid and polymer nanoparticle formulations that can most effectively deliver mRNA to cells, using machine learning to help identify the best candidates. They will also develop and test ingestible devices to carry the mRNA-nanoparticle payload, with the goal of running a clinical trial in the final year of the five-year project.

The work will build on research that Traverso’s lab has already begun. In 2022, Traverso and his colleagues reported that they could deliver mRNA in capsules that inject mRNA-nanoparticle complexes into the lining of the stomach.

The other branch of the project will focus on ingestible devices that can deliver a small electrical current to the lining of the stomach. In a study published last year, Traverso’s lab demonstrated this approach for the first time, using a capsule coated with electrodes that apply an electrical current to cells of the stomach. In animal studies, they found that this stimulation boosted production of ghrelin, a hormone that stimulates appetite.

Traverso envisions that this type of treatment could potentially replace or complement some of the existing drugs used to prevent nausea and stimulate appetite in people with anorexia or cachexia (loss of body mass that can occur in patients with cancer or other chronic diseases). The researchers also hope to develop ways to stimulate production of GLP-1, a hormone that is used to help manage diabetes and promote weight loss.

“What this approach starts to do is potentially maximize our ability to treat disease without administering a new drug, but instead by simply modulating the body’s own systems through electrical stimulation,” Traverso says.

At MIT, Langer will help to develop nanoparticles for mRNA delivery, and Chandrakasan will work on ways to reduce energy consumption and miniaturize the electronic functions of the capsules, including secure communication, stimulation, and power generation.

The Brigham and Women’s Hospital’s portion of the project will be co-led by Traverso, Ameya Kirtane, Jason Li, and Peter Chai, who will amplify efforts on the formulation and stabilization of the mRNA nanoparticles, engineering of the ingestible devices, and running of clinical trials. At NYU, the effort will be led by assistant professor of bioengineering Khalil Ramadi SM ’16, PhD ’19, focusing on biological characterization of the effects of electrical stimulation. Researchers at the University of Colorado, led by Matthew Wynia and Eric G. Campbell of the CU Center for Bioethics and Humanities, will focus on exploring the ethical dimensions and public perceptions of these types of biomedical interventions.

“We felt like we had an opportunity here not only to do fundamental engineering science and early-stage clinical trials, but also to start to understand the data behind some of the ethical implications and public perceptions of these technologies through this broad collaboration,” Traverso says.

The project described here is supported by ARPA-H under award number D24AC00040-00. The content of this announcement does not necessarily represent the official views of the Advanced Research Projects Agency for Health.

© Image: Courtesy of MechE

Using a virus-like delivery particle made from DNA, researchers from MIT and the Ragon Institute of MGH, MIT, and Harvard have created a vaccine that can induce a strong antibody response against SARS-CoV-2.

The vaccine, which has been tested in mice, consists of a DNA scaffold that carries many copies of a viral antigen. This type of vaccine, known as a particulate vaccine, mimics the structure of a virus. Most previous work on particulate vaccines has relied on protein scaffolds, but the proteins used in those vaccines tend to generate an unnecessary immune response that can distract the immune system from the target.

In the mouse study, the researchers found that the DNA scaffold does not induce an immune response, allowing the immune system to focus its antibody response on the target antigen.

“DNA, we found in this work, does not elicit antibodies that may distract away from the protein of interest,” says Mark Bathe, an MIT professor of biological engineering. “What you can imagine is that your B cells and immune system are being fully trained by that target antigen, and that’s what you want — for your immune system to be laser-focused on the antigen of interest.”

This approach, which strongly stimulates B cells (the cells that produce antibodies), could make it easier to develop vaccines against viruses that have been difficult to target, including HIV and influenza, as well as SARS-CoV-2, the researchers say. Unlike T cells, which are stimulated by other types of vaccines, these B cells can persist for decades, offering long-term protection.

“We’re interested in exploring whether we can teach the immune system to deliver higher levels of immunity against pathogens that resist conventional vaccine approaches, like flu, HIV, and SARS-CoV-2,” says Daniel Lingwood, an associate professor at Harvard Medical School and a principal investigator at the Ragon Institute. “This idea of decoupling the response against the target antigen from the platform itself is a potentially powerful immunological trick that one can now bring to bear to help those immunological targeting decisions move in a direction that is more focused.”

Bathe, Lingwood, and Aaron Schmidt, an associate professor at Harvard Medical School and principal investigator at the Ragon Institute, are the senior authors of the paper, which appears today in Nature Communications. The paper’s lead authors are Eike-Christian Wamhoff, a former MIT postdoc; Larance Ronsard, a Ragon Institute postdoc; Jared Feldman, a former Harvard University graduate student; Grant Knappe, an MIT graduate student; and Blake Hauser, a former Harvard graduate student. 

Mimicking viruses

Particulate vaccines usually consist of a protein nanoparticle, similar in structure to a virus, that can carry many copies of a viral antigen. This high density of antigens can lead to a stronger immune response than traditional vaccines because the body sees it as similar to an actual virus. Particulate vaccines have been developed for a handful of pathogens, including hepatitis B and human papillomavirus, and a particulate vaccine for SARS-CoV-2 has been approved for use in South Korea.

These vaccines are especially good at activating B cells, which produce antibodies specific to the vaccine antigen.

“Particulate vaccines are of great interest for many in immunology because they give you robust humoral immunity, which is antibody-based immunity, which is differentiated from the T-cell-based immunity that the mRNA vaccines seem to elicit more strongly,” Bathe says.

A potential drawback to this kind of vaccine, however, is that the proteins used for the scaffold often stimulate the body to produce antibodies targeting the scaffold. This can distract the immune system and prevent it from launching as robust a response as one would like, Bathe says.

“To neutralize the SARS-CoV-2 virus, you want to have a vaccine that generates antibodies toward the receptor binding domain portion of the virus’ spike protein,” he says. “When you display that on a protein-based particle, what happens is your immune system recognizes not only that receptor binding domain protein, but all the other proteins that are irrelevant to the immune response you’re trying to elicit.”

Another potential drawback is that if the same person receives more than one vaccine carried by the same protein scaffold, for example, SARS-CoV-2 and then influenza, their immune system would likely respond right away to the protein scaffold, having already been primed to react to it. This could weaken the immune response to the antigen carried by the second vaccine.

“If you want to apply that protein-based particle to immunize against a different virus like influenza, then your immune system can be addicted to the underlying protein scaffold that it’s already seen and developed an immune response toward,” Bathe says. “That can hypothetically diminish the quality of your antibody response for the actual antigen of interest.”

As an alternative, Bathe’s lab has been developing scaffolds made using DNA origami, a method that offers precise control over the structure of synthetic DNA and allows researchers to attach a variety of molecules, such as viral antigens, at specific locations.

In a 2020 study, Bathe and Darrell Irvine, an MIT professor of biological engineering and of materials science and engineering, showed that a DNA scaffold carrying 30 copies of an HIV antigen could generate a strong antibody response in B cells grown in the lab. This type of structure is optimal for activating B cells because it closely mimics the structure of nano-sized viruses, which display many copies of viral proteins in their surfaces.

“This approach builds off of a fundamental principle in B-cell antigen recognition, which is that if you have an arrayed display of the antigen, that promotes B-cell responses and gives better quantity and quality of antibody output,” Lingwood says.

“Immunologically silent”

In the new study, the researchers swapped in an antigen consisting of the receptor binding protein of the spike protein from the original strain of SARS-CoV-2. When they gave the vaccine to mice, they found that the mice generated high levels of antibodies to the spike protein but did not generate any to the DNA scaffold.

In contrast, a vaccine based on a scaffold protein called ferritin, coated with SARS-CoV-2 antigens, generated many antibodies against ferritin as well as SARS-CoV-2.

“The DNA nanoparticle itself is immunogenically silent,” Lingwood says. “If you use a protein-based platform, you get equally high titer antibody responses to the platform and to the antigen of interest, and that can complicate repeated usage of that platform because you’ll develop high affinity immune memory against it.”

Reducing these off-target effects could also help scientists reach the goal of developing a vaccine that would induce broadly neutralizing antibodies to any variant of SARS-CoV-2, or even to all sarbecoviruses, the subgenus of virus that includes SARS-CoV-2 as well as the viruses that cause SARS and MERS.

To that end, the researchers are now exploring whether a DNA scaffold with many different viral antigens attached could induce broadly neutralizing antibodies against SARS-CoV-2 and related viruses. 

The research was primarily funded by the National Institutes of Health, the National Science Foundation, and the Fast Grants program.

© Credit: The Bathe Lab

Tumors constantly shed DNA from dying cells, which briefly circulates in the patient’s bloodstream before it is quickly broken down. Many companies have created blood tests that can pick out this tumor DNA, potentially helping doctors diagnose or monitor cancer or choose a treatment.

The amount of tumor DNA circulating at any given time, however, is extremely small, so it has been challenging to develop tests sensitive enough to pick up that tiny signal. A team of researchers from MIT and the Broad Institute of MIT and Harvard has now come up with a way to significantly boost that signal, by temporarily slowing the clearance of tumor DNA circulating in the bloodstream.

The researchers developed two different types of injectable molecules that they call “priming agents,” which can transiently interfere with the body’s ability to remove circulating tumor DNA from the bloodstream. In a study of mice, they showed that these agents could boost DNA levels enough that the percentage of detectable early-stage lung metastases leapt from less than 10 percent to above 75 percent.

This approach could enable not only earlier diagnosis of cancer, but also more sensitive detection of tumor mutations that could be used to guide treatment. It could also help improve detection of cancer recurrence.

“You can give one of these agents an hour before the blood draw, and it makes things visible that previously wouldn’t have been. The implication is that we should be able to give everybody who’s doing liquid biopsies, for any purpose, more molecules to work with,” says Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and of Electrical Engineering and Computer Science at MIT, and a member of MIT’s Koch Institute for Integrative Cancer Research and the Institute for Medical Engineering and Science.

Bhatia is one of the senior authors of the new study, along with J. Christopher Love, the Raymond A. and Helen E. St. Laurent Professor of Chemical Engineering at MIT and a member of the Koch Institute and the Ragon Institute of MGH, MIT, and Harvard and Viktor Adalsteinsson, director of the Gerstner Center for Cancer Diagnostics at the Broad Institute.

Carmen Martin-Alonso PhD ’23, MIT and Broad Institute postdoc Shervin Tabrizi, and Broad Institute scientist Kan Xiong are the lead authors of the paper, which appears today in Science.

Better biopsies

Liquid biopsies, which enable detection of small quantities of DNA in blood samples, are now used in many cancer patients to identify mutations that could help guide treatment. With greater sensitivity, however, these tests could become useful for far more patients. Most efforts to improve the sensitivity of liquid biopsies have focused on developing new sequencing technologies to use after the blood is drawn.

While brainstorming ways to make liquid biopsies more informative, Bhatia, Love, Adalsteinsson, and their trainees came up with the idea of trying to increase the amount of DNA in a patient’s bloodstream before the sample is taken.

“A tumor is always creating new cell-free DNA, and that’s the signal that we’re attempting to detect in the blood draw. Existing liquid biopsy technologies, however, are limited by the amount of material you collect in the tube of blood,” Love says. “Where this work intercedes is thinking about how to inject something beforehand that would help boost or enhance the amount of signal that is available to collect in the same small sample.”

The body uses two primary strategies to remove circulating DNA from the bloodstream. Enzymes called DNases circulate in the blood and break down DNA that they encounter, while immune cells known as macrophages take up cell-free DNA as blood is filtered through the liver.

The researchers decided to target each of these processes separately. To prevent DNases from breaking down DNA, they designed a monoclonal antibody that binds to circulating DNA and protects it from the enzymes.

“Antibodies are well-established biopharmaceutical modalities, and they’re safe in a number of different disease contexts, including cancer and autoimmune treatments,” Love says. “The idea was, could we use this kind of antibody to help shield the DNA temporarily from degradation by the nucleases that are in circulation? And by doing so, we shift the balance to where the tumor is generating DNA slightly faster than is being degraded, increasing the concentration in a blood draw.”

The other priming agent they developed is a nanoparticle designed to block macrophages from taking up cell-free DNA. These cells have a well-known tendency to eat up synthetic nanoparticles.

“DNA is a biological nanoparticle, and it made sense that immune cells in the liver were probably taking this up just like they do synthetic nanoparticles. And if that were the case, which it turned out to be, then we could use a safe dummy nanoparticle to distract those immune cells and leave the circulating DNA alone so that it could be at a higher concentration,” Bhatia says.

Earlier tumor detection

The researchers tested their priming agents in mice that received transplants of cancer cells that tend to form tumors in the lungs. Two weeks after the cells were transplanted, the researchers showed that these priming agents could boost the amount of circulating tumor DNA recovered in a blood sample by up to 60-fold.

Once the blood sample is taken, it can be run through the same kinds of sequencing tests now used on liquid biopsy samples. These tests can pick out tumor DNA, including specific sequences used to determine the type of tumor and potentially what kinds of treatments would work best.

Early detection of cancer is another promising application for these priming agents. The researchers found that when mice were given the nanoparticle priming agent before blood was drawn, it allowed them to detect circulating tumor DNA in blood of 75 percent of the mice with low cancer burden, while none were detectable without this boost.

“One of the greatest hurdles for cancer liquid biopsy testing has been the scarcity of circulating tumor DNA in a blood sample,” Adalsteinsson says. “It’s thus been encouraging to see the magnitude of the effect we’ve been able to achieve so far and to envision what impact this could have for patients.”

After either of the priming agents are injected, it takes an hour or two for the DNA levels to increase in the bloodstream, and then they return to normal within about 24 hours.

“The ability to get peak activity of these agents within a couple of hours, followed by their rapid clearance, means that someone could go into a doctor’s office, receive an agent like this, and then give their blood for the test itself, all within one visit,” Love says. “This feature bodes well for the potential to translate this concept into clinical use.”

The researchers have launched a company called Amplifyer Bio that plans to further develop the technology, in hopes of advancing to clinical trials.

“A tube of blood is a much more accessible diagnostic than colonoscopy screening or even mammography,” Bhatia says. “Ultimately, if these tools really are predictive, then we should be able to get many more patients into the system who could benefit from cancer interception or better therapy.”

The research was funded by the Koch Institute Support (core) Grant from the National Cancer Institute, the Marble Center for Cancer Nanomedicine, the Gerstner Family Foundation, the Ludwig Center at MIT, the Koch Institute Frontier Research Program via the Casey and Family Foundation, and the Bridge Project, a partnership between the Koch Institute and the Dana-Farber/Harvard Cancer Center.

© Image: MIT News; iStock

When Paula Hammond first arrived on MIT’s campus as a first-year student in the early 1980s, she wasn’t sure if she belonged. In fact, as she told an MIT audience yesterday, she felt like “an imposter.”

However, that feeling didn’t last long, as Hammond began to find support among her fellow students and MIT’s faculty. “Community was really important for me, to feel that I belonged, to feel that I had a place here, and I found people who were willing to embrace me and support me,” she said.

Hammond, a world-renowned chemical engineer who has spent most of her academic career at MIT, made her remarks during the 2023-24 James R. Killian Jr. Faculty Achievement Award lecture.

Established in 1971 to honor MIT’s 10th president, James Killian, the Killian Award recognizes extraordinary professional achievements by an MIT faculty member. Hammond was chosen for this year’s award “not only for her tremendous professional achievements and contributions, but also for her genuine warmth and humanity, her thoughtfulness and effective leadership, and her empathy and ethics,” according to the award citation.

“Professor Hammond is a pioneer in nanotechnology research. With a program that extends from basic science to translational research in medicine and energy, she has introduced new approaches for the design and development of complex drug delivery systems for cancer treatment and noninvasive imaging,” said Mary Fuller, chair of MIT’s faculty and a professor of literature, who presented the award. “As her colleagues, we are delighted to celebrate her career today.”

In January, Hammond began serving as MIT’s vice provost for faculty. Before that, she chaired the Department of Chemical Engineering for eight years, and she was named an Institute Professor in 2021.

A versatile technique

Hammond, who grew up in Detroit, credits her parents with instilling a love of science. Her father was one of very few Black PhDs in biochemistry at the time, while her mother earned a master’s degree in nursing from Howard University and founded the nursing school at Wayne County Community College. “That provided a huge amount of opportunity for women in the area of Detroit, including women of color,” Hammond noted.

After earning her bachelor’s degree from MIT in 1984, Hammond worked as an engineer before returning to the Institute as a graduate student, earning her PhD in 1993. After a two-year postdoc at Harvard University, she returned to join the MIT faculty in 1995.

At the heart of Hammond’s research is a technique she developed to create thin films that can essentially “shrink-wrap” nanoparticles. By tuning the chemical composition of these films, the particles can be customized to deliver drugs or nucleic acids and to target specific cells in the body, including cancer cells.

To make these films, Hammond begins by layering positively charged polymers onto a negatively charged surface. Then, more layers can be added, alternating positively and negatively charged polymers. Each of these layers may contain drugs or other useful molecules, such as DNA or RNA. Some of these films contain hundreds of layers, others just one, making them useful for a wide range of applications.

“What’s nice about the layer-by-layer process is I can choose a group of degradable polymers that are nicely biocompatible, and I can alternate them with our drug materials. This means that I can build up thin film layers that contain different drugs at different points within the film,” Hammond said. “Then, when the film degrades, it can release those drugs in reverse order. This is enabling us to create complex, multidrug films, using a simple water-based technique.”

Hammond described how these layer-by-layer films can be used to promote bone growth, in an application that could help people born with congenital bone defects or people who experience traumatic injuries.

For that use, her lab has created films with layers of two proteins. One of these, BMP-2, is a protein that interacts with adult stem cells and induces them to differentiate into bone cells, generating new bone. The second is a growth factor called VEGF, which stimulates the growth of new blood vessels that help bone to regenerate. These layers are applied to a very thin tissue scaffold that can be implanted at the injury site.

Hammond and her students designed the coating so that once implanted, it would release VEGF early, over a week or so, and continue releasing BMP-2 for up to 40 days. In a study of mice, they found that this tissue scaffold stimulated the growth of new bone that was nearly indistinguishable from natural bone.

Targeting cancer

As a member of MIT’s Koch Institute for Integrative Cancer Research, Hammond has also developed layer-by-layer coatings that can improve the performance of nanoparticles used for cancer drug delivery, such as liposomes or nanoparticles made from a polymer called PLGA.

“We have a broad range of drug carriers that we can wrap this way. I think of them like a gobstopper, where there are all those different layers of candy and they dissolve one at a time,” Hammond said.

Using this approach, Hammond has created particles that can deliver a one-two punch to cancer cells. First, the particles release a dose of a nucleic acid such as short interfering RNA (siRNA), which can turn off a cancerous gene, or microRNA, which can activate tumor suppressor genes. Then, the particles release a chemotherapy drug such as cisplatin, to which the cells are now more vulnerable.

The particles also include a negatively charged outer “stealth layer” that protects them from being broken down in the bloodstream before they can reach their targets. This outer layer can also be modified to help the particles get taken up by cancer cells, by incorporating molecules that bind to proteins that are abundant on tumor cells.

In more recent work, Hammond has begun developing nanoparticles that can target ovarian cancer and help prevent recurrence of the disease after chemotherapy. In about 70 percent of ovarian cancer patients, the first round of treatment is highly effective, but tumors recur in about 85 percent of those cases, and these new tumors are usually highly drug resistant.

By altering the type of coating applied to drug-delivering nanoparticles, Hammond has found that the particles can be designed to either get inside tumor cells or stick to their surfaces. Using particles that stick to the cells, she has designed a treatment that could help to jumpstart a patient’s immune response to any recurrent tumor cells.

“With ovarian cancer, very few immune cells exist in that space, and because they don’t have a lot of immune cells present, it’s very difficult to rev up an immune response,” she said. “However, if we can deliver a molecule to neighboring cells, those few that are present, and get them revved up, then we might be able to do something.”

To that end, she designed nanoparticles that deliver IL-12, a cytokine that stimulates nearby T cells to spring into action and begin attacking tumor cells. In a study of mice, she found that this treatment induced a long-term memory T-cell response that prevented recurrence of ovarian cancer.

Hammond closed her lecture by describing the impact that the Institute has had on her throughout her career.

“It’s been a transformative experience,” she said. “I really think of this place as special because it brings people together and enables us to do things together that we couldn’t do alone. And it is that support we get from our friends, our colleagues, and our students that really makes things possible.”

© Photo: Jake Belcher

Many vaccines, including vaccines for hepatitis B and whooping cough, consist of fragments of viral or bacterial proteins. These vaccines often include other molecules called adjuvants, which help to boost the immune system’s response to the protein.

Most of these adjuvants consist of aluminum salts or other molecules that provoke a nonspecific immune response. A team of MIT researchers has now shown that a type of nanoparticle called a metal organic framework (MOF) can also provoke a strong immune response, by activating the innate immune system — the body’s first line of defense against any pathogen — through cell proteins called toll-like receptors.

In a study of mice, the researchers showed that this MOF could successfully encapsulate and deliver part of the SARS-CoV-2 spike protein, while also acting as an adjuvant once the MOF is broken down inside cells.

While more work would be needed to adapt these particles for use as vaccines, the study demonstrates that this type of structure can be useful for generating a strong immune response, the researchers say.

“Understanding how the drug delivery vehicle can enhance an adjuvant immune response is something that could be very helpful in designing new vaccines,” says Ana Jaklenec, a principal investigator at MIT’s Koch Institute for Integrative Cancer Research and one of the senior authors of the new study.

Robert Langer, an MIT Institute Professor and member of the Koch Institute, and Dan Barouch, director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center and a professor at Harvard Medical School, are also senior authors of the paper, which appears today in Science Advances. The paper’s lead author is former MIT postdoc and Ibn Khaldun Fellow Shahad Alsaiari.

Immune activation

In this study, the researchers focused on a MOF called ZIF-8, which consists of a lattice of tetrahedral units made up of a zinc ion attached to four molecules of imidazole, an organic compound. Previous work has shown that ZIF-8 can significantly boost immune responses, but it wasn’t known exactly how this particle activates the immune system.

To try to figure that out, the MIT team created an experimental vaccine consisting of the SARS-CoV-2 receptor-binding protein (RBD) embedded within ZIF-8 particles. These particles are between 100 and 200 nanometers in diameter, a size that allows them to get into the body’s lymph nodes directly or through immune cells such as macrophages.

Once the particles enter the cells, the MOFs are broken down, releasing the viral proteins. The researchers found that the imidazole components then activate toll-like receptors (TLRs), which help to stimulate the innate immune response.

“This process is analogous to establishing a covert operative team at the molecular level to transport essential elements of the Covid-19 virus to the body’s immune system, where they can activate specific immune responses to boost vaccine efficacy,” Alsaiari says.

RNA sequencing of cells from the lymph nodes showed that mice vaccinated with ZIF-8 particles carrying the viral protein strongly activated a TLR pathway known as TLR-7, which led to greater production of cytokines and other molecules involved in inflammation.

Mice vaccinated with these particles generated a much stronger response to the viral protein than mice that received the protein on its own.

“Not only are we delivering the protein in a more controlled way through a nanoparticle, but the compositional structure of this particle is also acting as an adjuvant,” Jaklenec says. “We were able to achieve very specific responses to the Covid protein, and with a dose-sparing effect compared to using the protein by itself to vaccinate.”

Vaccine access

While this study and others have demonstrated ZIF-8’s immunogenic ability, more work needs to be done to evaluate the particles’ safety and potential to be scaled up for large-scale manufacturing. If ZIF-8 is not developed as a vaccine carrier, the findings from the study should help to guide researchers in developing similar nanoparticles that could be used to deliver subunit vaccines, Jaklenec says.

“Most subunit vaccines usually have two separate components: an antigen and an adjuvant,” Jaklenec says. “Designing new vaccines that utilize nanoparticles with specific chemical moieties which not only aid in antigen delivery but can also activate particular immune pathways have the potential to enhance vaccine potency.”

One advantage to developing a subunit vaccine for Covid-19 is that such vaccines are usually easier and cheaper to manufacture than mRNA vaccines, which could make it easier to distribute them around the world, the researchers say.

“Subunit vaccines have been around for a long time, and they tend to be cheaper to produce, so that opens up more access to vaccines, especially in times of pandemic,” Jaklenec says.

The research was funded by Ibn Khaldun Fellowships for Saudi Arabian Women and in part by the Koch Institute Support (core) Grant from the U.S. National Cancer Institute.

© Image: Courtesy of the researchers

A team of MIT researchers will lead a $65.67 million effort, awarded by the U.S. Advanced Research Projects Agency for Health (ARPA-H), to develop ingestible devices that may one day be used to treat diabetes, obesity, and other conditions through oral delivery of mRNA. Such devices could potentially be deployed for needle-free delivery of mRNA vaccines as well.

The five-year project also aims to develop electroceuticals, a new form of ingestible therapies based on electrical stimulation of the body’s own hormones and neural signaling. If successful, this approach could lead to new treatments for a variety of metabolic disorders.

“We know that the oral route is generally the preferred route of administration for both patients and health care providers,” says Giovanni Traverso, an associate professor of mechanical engineering at MIT and a gastroenterologist at Brigham and Women’s Hospital. “Our primary focus is on disorders of metabolism because they affect a lot of people, but the platforms we’re developing could be applied very broadly.”

Traverso is the principal investigator for the project, which also includes Robert Langer, MIT Institute Professor, and Anantha Chandrakasan, dean of the MIT School of Engineering and the Vannevar Bush Professor of Electrical Engineering and Computer Science. As part of the project, the MIT team will collaborate with investigators from Brigham and Women’s Hospital, New York University, and the University of Colorado School of Medicine.

Over the past several years, Traverso’s and Langer’s labs have designed many types of ingestible devices that can deliver drugs to the GI tract. This approach could be especially useful for protein drugs and nucleic acids, which typically can’t be given orally because they break down in the acidic environment of the digestive tract.

Messenger RNA has already proven useful as a vaccine, directing cells to produce fragments of viral proteins that trigger an immune response. Delivering mRNA to cells also holds potential to stimulate production of therapeutic molecules to treat a variety of diseases. In this project, the researchers plan to focus on metabolic diseases such as diabetes.

“What mRNA can do is enable the potential for dosing therapies that are very difficult to dose today, or provide longer-term coverage by essentially creating an internal factory that produces a therapy for a prolonged period,” Traverso says.

In the mRNA portion of the project, the research team intends to identify lipid and polymer nanoparticle formulations that can most effectively deliver mRNA to cells, using machine learning to help identify the best candidates. They will also develop and test ingestible devices to carry the mRNA-nanoparticle payload, with the goal of running a clinical trial in the final year of the five-year project.

The work will build on research that Traverso’s lab has already begun. In 2022, Traverso and his colleagues reported that they could deliver mRNA in capsules that inject mRNA-nanoparticle complexes into the lining of the stomach.

The other branch of the project will focus on ingestible devices that can deliver a small electrical current to the lining of the stomach. In a study published last year, Traverso’s lab demonstrated this approach for the first time, using a capsule coated with electrodes that apply an electrical current to cells of the stomach. In animal studies, they found that this stimulation boosted production of ghrelin, a hormone that stimulates appetite.

Traverso envisions that this type of treatment could potentially replace or complement some of the existing drugs used to prevent nausea and stimulate appetite in people with anorexia or cachexia (loss of body mass that can occur in patients with cancer or other chronic diseases). The researchers also hope to develop ways to stimulate production of GLP-1, a hormone that is used to help manage diabetes and promote weight loss.

“What this approach starts to do is potentially maximize our ability to treat disease without administering a new drug, but instead by simply modulating the body’s own systems through electrical stimulation,” Traverso says.

At MIT, Langer will help to develop nanoparticles for mRNA delivery, and Chandrakasan will work on ways to reduce energy consumption and miniaturize the electronic functions of the capsules, including secure communication, stimulation, and power generation.

The Brigham and Women’s Hospital’s portion of the project will be co-led by Traverso, Ameya Kirtane, Jason Li, and Peter Chai, who will amplify efforts on the formulation and stabilization of the mRNA nanoparticles, engineering of the ingestible devices, and running of clinical trials. At NYU, the effort will be led by assistant professor of bioengineering Khalil Ramadi SM ’16, PhD ’19, focusing on biological characterization of the effects of electrical stimulation. Researchers at the University of Colorado, led by Matthew Wynia and Eric G. Campbell of the CU Center for Bioethics and Humanities, will focus on exploring the ethical dimensions and public perceptions of these types of biomedical interventions.

“We felt like we had an opportunity here not only to do fundamental engineering science and early-stage clinical trials, but also to start to understand the data behind some of the ethical implications and public perceptions of these technologies through this broad collaboration,” Traverso says.

The project described here is supported by ARPA-H under award number D24AC00040-00. The content of this announcement does not necessarily represent the official views of the Advanced Research Projects Agency for Health.

© Image: Courtesy of MechE

Using a virus-like delivery particle made from DNA, researchers from MIT and the Ragon Institute of MGH, MIT, and Harvard have created a vaccine that can induce a strong antibody response against SARS-CoV-2.

The vaccine, which has been tested in mice, consists of a DNA scaffold that carries many copies of a viral antigen. This type of vaccine, known as a particulate vaccine, mimics the structure of a virus. Most previous work on particulate vaccines has relied on protein scaffolds, but the proteins used in those vaccines tend to generate an unnecessary immune response that can distract the immune system from the target.

In the mouse study, the researchers found that the DNA scaffold does not induce an immune response, allowing the immune system to focus its antibody response on the target antigen.

“DNA, we found in this work, does not elicit antibodies that may distract away from the protein of interest,” says Mark Bathe, an MIT professor of biological engineering. “What you can imagine is that your B cells and immune system are being fully trained by that target antigen, and that’s what you want — for your immune system to be laser-focused on the antigen of interest.”

This approach, which strongly stimulates B cells (the cells that produce antibodies), could make it easier to develop vaccines against viruses that have been difficult to target, including HIV and influenza, as well as SARS-CoV-2, the researchers say. Unlike T cells, which are stimulated by other types of vaccines, these B cells can persist for decades, offering long-term protection.

“We’re interested in exploring whether we can teach the immune system to deliver higher levels of immunity against pathogens that resist conventional vaccine approaches, like flu, HIV, and SARS-CoV-2,” says Daniel Lingwood, an associate professor at Harvard Medical School and a principal investigator at the Ragon Institute. “This idea of decoupling the response against the target antigen from the platform itself is a potentially powerful immunological trick that one can now bring to bear to help those immunological targeting decisions move in a direction that is more focused.”

Bathe, Lingwood, and Aaron Schmidt, an associate professor at Harvard Medical School and principal investigator at the Ragon Institute, are the senior authors of the paper, which appears today in Nature Communications. The paper’s lead authors are Eike-Christian Wamhoff, a former MIT postdoc; Larance Ronsard, a Ragon Institute postdoc; Jared Feldman, a former Harvard University graduate student; Grant Knappe, an MIT graduate student; and Blake Hauser, a former Harvard graduate student. 

Mimicking viruses

Particulate vaccines usually consist of a protein nanoparticle, similar in structure to a virus, that can carry many copies of a viral antigen. This high density of antigens can lead to a stronger immune response than traditional vaccines because the body sees it as similar to an actual virus. Particulate vaccines have been developed for a handful of pathogens, including hepatitis B and human papillomavirus, and a particulate vaccine for SARS-CoV-2 has been approved for use in South Korea.

These vaccines are especially good at activating B cells, which produce antibodies specific to the vaccine antigen.

“Particulate vaccines are of great interest for many in immunology because they give you robust humoral immunity, which is antibody-based immunity, which is differentiated from the T-cell-based immunity that the mRNA vaccines seem to elicit more strongly,” Bathe says.

A potential drawback to this kind of vaccine, however, is that the proteins used for the scaffold often stimulate the body to produce antibodies targeting the scaffold. This can distract the immune system and prevent it from launching as robust a response as one would like, Bathe says.

“To neutralize the SARS-CoV-2 virus, you want to have a vaccine that generates antibodies toward the receptor binding domain portion of the virus’ spike protein,” he says. “When you display that on a protein-based particle, what happens is your immune system recognizes not only that receptor binding domain protein, but all the other proteins that are irrelevant to the immune response you’re trying to elicit.”

Another potential drawback is that if the same person receives more than one vaccine carried by the same protein scaffold, for example, SARS-CoV-2 and then influenza, their immune system would likely respond right away to the protein scaffold, having already been primed to react to it. This could weaken the immune response to the antigen carried by the second vaccine.

“If you want to apply that protein-based particle to immunize against a different virus like influenza, then your immune system can be addicted to the underlying protein scaffold that it’s already seen and developed an immune response toward,” Bathe says. “That can hypothetically diminish the quality of your antibody response for the actual antigen of interest.”

As an alternative, Bathe’s lab has been developing scaffolds made using DNA origami, a method that offers precise control over the structure of synthetic DNA and allows researchers to attach a variety of molecules, such as viral antigens, at specific locations.

In a 2020 study, Bathe and Darrell Irvine, an MIT professor of biological engineering and of materials science and engineering, showed that a DNA scaffold carrying 30 copies of an HIV antigen could generate a strong antibody response in B cells grown in the lab. This type of structure is optimal for activating B cells because it closely mimics the structure of nano-sized viruses, which display many copies of viral proteins in their surfaces.

“This approach builds off of a fundamental principle in B-cell antigen recognition, which is that if you have an arrayed display of the antigen, that promotes B-cell responses and gives better quantity and quality of antibody output,” Lingwood says.

“Immunologically silent”

In the new study, the researchers swapped in an antigen consisting of the receptor binding protein of the spike protein from the original strain of SARS-CoV-2. When they gave the vaccine to mice, they found that the mice generated high levels of antibodies to the spike protein but did not generate any to the DNA scaffold.

In contrast, a vaccine based on a scaffold protein called ferritin, coated with SARS-CoV-2 antigens, generated many antibodies against ferritin as well as SARS-CoV-2.

“The DNA nanoparticle itself is immunogenically silent,” Lingwood says. “If you use a protein-based platform, you get equally high titer antibody responses to the platform and to the antigen of interest, and that can complicate repeated usage of that platform because you’ll develop high affinity immune memory against it.”

Reducing these off-target effects could also help scientists reach the goal of developing a vaccine that would induce broadly neutralizing antibodies to any variant of SARS-CoV-2, or even to all sarbecoviruses, the subgenus of virus that includes SARS-CoV-2 as well as the viruses that cause SARS and MERS.

To that end, the researchers are now exploring whether a DNA scaffold with many different viral antigens attached could induce broadly neutralizing antibodies against SARS-CoV-2 and related viruses. 

The research was primarily funded by the National Institutes of Health, the National Science Foundation, and the Fast Grants program.

© Credit: The Bathe Lab

Tumors constantly shed DNA from dying cells, which briefly circulates in the patient’s bloodstream before it is quickly broken down. Many companies have created blood tests that can pick out this tumor DNA, potentially helping doctors diagnose or monitor cancer or choose a treatment.

The amount of tumor DNA circulating at any given time, however, is extremely small, so it has been challenging to develop tests sensitive enough to pick up that tiny signal. A team of researchers from MIT and the Broad Institute of MIT and Harvard has now come up with a way to significantly boost that signal, by temporarily slowing the clearance of tumor DNA circulating in the bloodstream.

The researchers developed two different types of injectable molecules that they call “priming agents,” which can transiently interfere with the body’s ability to remove circulating tumor DNA from the bloodstream. In a study of mice, they showed that these agents could boost DNA levels enough that the percentage of detectable early-stage lung metastases leapt from less than 10 percent to above 75 percent.

This approach could enable not only earlier diagnosis of cancer, but also more sensitive detection of tumor mutations that could be used to guide treatment. It could also help improve detection of cancer recurrence.

“You can give one of these agents an hour before the blood draw, and it makes things visible that previously wouldn’t have been. The implication is that we should be able to give everybody who’s doing liquid biopsies, for any purpose, more molecules to work with,” says Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and of Electrical Engineering and Computer Science at MIT, and a member of MIT’s Koch Institute for Integrative Cancer Research and the Institute for Medical Engineering and Science.

Bhatia is one of the senior authors of the new study, along with J. Christopher Love, the Raymond A. and Helen E. St. Laurent Professor of Chemical Engineering at MIT and a member of the Koch Institute and the Ragon Institute of MGH, MIT, and Harvard and Viktor Adalsteinsson, director of the Gerstner Center for Cancer Diagnostics at the Broad Institute.

Carmen Martin-Alonso PhD ’23, MIT and Broad Institute postdoc Shervin Tabrizi, and Broad Institute scientist Kan Xiong are the lead authors of the paper, which appears today in Science.

Better biopsies

Liquid biopsies, which enable detection of small quantities of DNA in blood samples, are now used in many cancer patients to identify mutations that could help guide treatment. With greater sensitivity, however, these tests could become useful for far more patients. Most efforts to improve the sensitivity of liquid biopsies have focused on developing new sequencing technologies to use after the blood is drawn.

While brainstorming ways to make liquid biopsies more informative, Bhatia, Love, Adalsteinsson, and their trainees came up with the idea of trying to increase the amount of DNA in a patient’s bloodstream before the sample is taken.

“A tumor is always creating new cell-free DNA, and that’s the signal that we’re attempting to detect in the blood draw. Existing liquid biopsy technologies, however, are limited by the amount of material you collect in the tube of blood,” Love says. “Where this work intercedes is thinking about how to inject something beforehand that would help boost or enhance the amount of signal that is available to collect in the same small sample.”

The body uses two primary strategies to remove circulating DNA from the bloodstream. Enzymes called DNases circulate in the blood and break down DNA that they encounter, while immune cells known as macrophages take up cell-free DNA as blood is filtered through the liver.

The researchers decided to target each of these processes separately. To prevent DNases from breaking down DNA, they designed a monoclonal antibody that binds to circulating DNA and protects it from the enzymes.

“Antibodies are well-established biopharmaceutical modalities, and they’re safe in a number of different disease contexts, including cancer and autoimmune treatments,” Love says. “The idea was, could we use this kind of antibody to help shield the DNA temporarily from degradation by the nucleases that are in circulation? And by doing so, we shift the balance to where the tumor is generating DNA slightly faster than is being degraded, increasing the concentration in a blood draw.”

The other priming agent they developed is a nanoparticle designed to block macrophages from taking up cell-free DNA. These cells have a well-known tendency to eat up synthetic nanoparticles.

“DNA is a biological nanoparticle, and it made sense that immune cells in the liver were probably taking this up just like they do synthetic nanoparticles. And if that were the case, which it turned out to be, then we could use a safe dummy nanoparticle to distract those immune cells and leave the circulating DNA alone so that it could be at a higher concentration,” Bhatia says.

Earlier tumor detection

The researchers tested their priming agents in mice that received transplants of cancer cells that tend to form tumors in the lungs. Two weeks after the cells were transplanted, the researchers showed that these priming agents could boost the amount of circulating tumor DNA recovered in a blood sample by up to 60-fold.

Once the blood sample is taken, it can be run through the same kinds of sequencing tests now used on liquid biopsy samples. These tests can pick out tumor DNA, including specific sequences used to determine the type of tumor and potentially what kinds of treatments would work best.

Early detection of cancer is another promising application for these priming agents. The researchers found that when mice were given the nanoparticle priming agent before blood was drawn, it allowed them to detect circulating tumor DNA in blood of 75 percent of the mice with low cancer burden, while none were detectable without this boost.

“One of the greatest hurdles for cancer liquid biopsy testing has been the scarcity of circulating tumor DNA in a blood sample,” Adalsteinsson says. “It’s thus been encouraging to see the magnitude of the effect we’ve been able to achieve so far and to envision what impact this could have for patients.”

After either of the priming agents are injected, it takes an hour or two for the DNA levels to increase in the bloodstream, and then they return to normal within about 24 hours.

“The ability to get peak activity of these agents within a couple of hours, followed by their rapid clearance, means that someone could go into a doctor’s office, receive an agent like this, and then give their blood for the test itself, all within one visit,” Love says. “This feature bodes well for the potential to translate this concept into clinical use.”

The researchers have launched a company called Amplifyer Bio that plans to further develop the technology, in hopes of advancing to clinical trials.

“A tube of blood is a much more accessible diagnostic than colonoscopy screening or even mammography,” Bhatia says. “Ultimately, if these tools really are predictive, then we should be able to get many more patients into the system who could benefit from cancer interception or better therapy.”

The research was funded by the Koch Institute Support (core) Grant from the National Cancer Institute, the Marble Center for Cancer Nanomedicine, the Gerstner Family Foundation, the Ludwig Center at MIT, the Koch Institute Frontier Research Program via the Casey and Family Foundation, and the Bridge Project, a partnership between the Koch Institute and the Dana-Farber/Harvard Cancer Center.

© Image: MIT News; iStock

An MIT research team led by Professor Darrell Irvine has developed a novel kind of vaccine adjuvant: a nanoparticle that can help to stimulate the immune system to generate a stronger response to a vaccine. These nanoparticles contain saponin, a compound derived from the bark of the Chilean soapbark tree, along with a molecule called MPLA, each of which helps to activate the immune system.

The adjuvant has been incorporated into an experimental HIV vaccine that has shown promising results in animal studies, and this month, the first human volunteers will receive the vaccine as part of a phase 1 clinical trial run by the Consortium for HIV/AIDS Vaccine Development at the Scripps Research Institute. MIT News spoke with Irvine about why this project required an interdisciplinary approach, and what may lie ahead.

Q: What are the special features of the new nanoparticle adjuvant that help it create a more powerful immune response to vaccination? 

A: Most vaccines, such as the Covid-19 vaccines, are thought to protect us through B cells making protective antibodies. Development of an HIV vaccine has been made challenging by the fact that the B cells that are capable of evolving to produce protective antibodies — called broadly neutralizing antibodies — are very rare in the average person. Vaccine adjuvants are important in this scenario to ensure that when we immunize with an HIV antigen, these rare B cells become activated and get a chance to participate in the immune response.

We particularly discovered that this new adjuvant, which we call SMNP (short for saponin/MPLA nanoparticles), is particularly good at helping more B cells enter germinal centers, the specialized location in lymph nodes where high affinity antibodies are produced. In animal models, SMNP also has shown unique mechanisms of action: Administering antigens with SMNP leads to better antigen delivery to lymph nodes (through increases in lymph flow) and better capture of the antigen by B cells in lymph nodes.

Q: How did your lab, which generally focuses on bioengineering and materials science, end up working on HIV vaccines? What obstacles did you have to overcome in the development of this adjuvant?

A: About 15 years ago, Bruce Walker approached me about getting involved in the HIV vaccine effort, and recruited me to join the Ragon Institute of MGH, MIT, and Harvard as a member of the steering committee. Through the Ragon Institute, I met colleagues in the Scripps Consortium for HIV/AIDS Vaccine Development (CHAVD), and we realized there was a tremendous opportunity to directly contribute to the HIV vaccine challenge, working in partnership with experts in immunogen design, structural biology, and HIV pathogenesis.

As we carried out study after study of SMNP in preclinical animal models, we realized the adjuvant had really amazing effects for promoting anti-HIV antibody responses, and the CHAVD decided this was worth moving forward to testing in humans. A major challenge was transferring the technology out of the lab to synthesize large amounts of the adjuvant under GMP (good manufacturing process) conditions for a clinical trial. The initial contract manufacturing organization (CMO) hired by the consortium to produce SMNP simply couldn’t get a process to work for scalable manufacturing.

Luckily for us, a chemical engineering graduate student, Ivan Pires, whom I co-advise with Paula Hammond, head of MIT’s Department of Chemical Engineering, had developed expertise in one particular processing technique known as tangential flow filtration during his undergraduate training. Leveraging classic chemical engineering skills in thermodynamics and process design, Ivan stepped in and solved the process issues the CMO was facing, allowing the manufacturing to move forward. This to me is what makes MIT great — the ability of our students and postdocs to step up and solve big problems and make big contributions when the need arises.

Q: What other diseases could this approach be useful for? Are there any plans to test it with other types of vaccines?

A: In principle, SMNP may be helpful for any infectious disease vaccine where strong antibody responses are needed. We are currently sharing the adjuvant with about 30 different labs around the world, who are testing it in vaccines against many other pathogens including Epstein-Barr virus, malaria, and influenza. We are hopeful that if SMNP is safe and effective in humans, this will be an adjuvant that can be broadly used in infectious disease trials.

© Photo: Steve Boxall

When Paula Hammond first arrived on MIT’s campus as a first-year student in the early 1980s, she wasn’t sure if she belonged. In fact, as she told an MIT audience yesterday, she felt like “an imposter.”

However, that feeling didn’t last long, as Hammond began to find support among her fellow students and MIT’s faculty. “Community was really important for me, to feel that I belonged, to feel that I had a place here, and I found people who were willing to embrace me and support me,” she said.

Hammond, a world-renowned chemical engineer who has spent most of her academic career at MIT, made her remarks during the 2023-24 James R. Killian Jr. Faculty Achievement Award lecture.

Established in 1971 to honor MIT’s 10th president, James Killian, the Killian Award recognizes extraordinary professional achievements by an MIT faculty member. Hammond was chosen for this year’s award “not only for her tremendous professional achievements and contributions, but also for her genuine warmth and humanity, her thoughtfulness and effective leadership, and her empathy and ethics,” according to the award citation.

“Professor Hammond is a pioneer in nanotechnology research. With a program that extends from basic science to translational research in medicine and energy, she has introduced new approaches for the design and development of complex drug delivery systems for cancer treatment and noninvasive imaging,” said Mary Fuller, chair of MIT’s faculty and a professor of literature, who presented the award. “As her colleagues, we are delighted to celebrate her career today.”

In January, Hammond began serving as MIT’s vice provost for faculty. Before that, she chaired the Department of Chemical Engineering for eight years, and she was named an Institute Professor in 2021.

A versatile technique

Hammond, who grew up in Detroit, credits her parents with instilling a love of science. Her father was one of very few Black PhDs in biochemistry at the time, while her mother earned a master’s degree in nursing from Howard University and founded the nursing school at Wayne County Community College. “That provided a huge amount of opportunity for women in the area of Detroit, including women of color,” Hammond noted.

After earning her bachelor’s degree from MIT in 1984, Hammond worked as an engineer before returning to the Institute as a graduate student, earning her PhD in 1993. After a two-year postdoc at Harvard University, she returned to join the MIT faculty in 1995.

At the heart of Hammond’s research is a technique she developed to create thin films that can essentially “shrink-wrap” nanoparticles. By tuning the chemical composition of these films, the particles can be customized to deliver drugs or nucleic acids and to target specific cells in the body, including cancer cells.

To make these films, Hammond begins by layering positively charged polymers onto a negatively charged surface. Then, more layers can be added, alternating positively and negatively charged polymers. Each of these layers may contain drugs or other useful molecules, such as DNA or RNA. Some of these films contain hundreds of layers, others just one, making them useful for a wide range of applications.

“What’s nice about the layer-by-layer process is I can choose a group of degradable polymers that are nicely biocompatible, and I can alternate them with our drug materials. This means that I can build up thin film layers that contain different drugs at different points within the film,” Hammond said. “Then, when the film degrades, it can release those drugs in reverse order. This is enabling us to create complex, multidrug films, using a simple water-based technique.”

Hammond described how these layer-by-layer films can be used to promote bone growth, in an application that could help people born with congenital bone defects or people who experience traumatic injuries.

For that use, her lab has created films with layers of two proteins. One of these, BMP-2, is a protein that interacts with adult stem cells and induces them to differentiate into bone cells, generating new bone. The second is a growth factor called VEGF, which stimulates the growth of new blood vessels that help bone to regenerate. These layers are applied to a very thin tissue scaffold that can be implanted at the injury site.

Hammond and her students designed the coating so that once implanted, it would release VEGF early, over a week or so, and continue releasing BMP-2 for up to 40 days. In a study of mice, they found that this tissue scaffold stimulated the growth of new bone that was nearly indistinguishable from natural bone.

Targeting cancer

As a member of MIT’s Koch Institute for Integrative Cancer Research, Hammond has also developed layer-by-layer coatings that can improve the performance of nanoparticles used for cancer drug delivery, such as liposomes or nanoparticles made from a polymer called PLGA.

“We have a broad range of drug carriers that we can wrap this way. I think of them like a gobstopper, where there are all those different layers of candy and they dissolve one at a time,” Hammond said.

Using this approach, Hammond has created particles that can deliver a one-two punch to cancer cells. First, the particles release a dose of a nucleic acid such as short interfering RNA (siRNA), which can turn off a cancerous gene, or microRNA, which can activate tumor suppressor genes. Then, the particles release a chemotherapy drug such as cisplatin, to which the cells are now more vulnerable.

The particles also include a negatively charged outer “stealth layer” that protects them from being broken down in the bloodstream before they can reach their targets. This outer layer can also be modified to help the particles get taken up by cancer cells, by incorporating molecules that bind to proteins that are abundant on tumor cells.

In more recent work, Hammond has begun developing nanoparticles that can target ovarian cancer and help prevent recurrence of the disease after chemotherapy. In about 70 percent of ovarian cancer patients, the first round of treatment is highly effective, but tumors recur in about 85 percent of those cases, and these new tumors are usually highly drug resistant.

By altering the type of coating applied to drug-delivering nanoparticles, Hammond has found that the particles can be designed to either get inside tumor cells or stick to their surfaces. Using particles that stick to the cells, she has designed a treatment that could help to jumpstart a patient’s immune response to any recurrent tumor cells.

“With ovarian cancer, very few immune cells exist in that space, and because they don’t have a lot of immune cells present, it’s very difficult to rev up an immune response,” she said. “However, if we can deliver a molecule to neighboring cells, those few that are present, and get them revved up, then we might be able to do something.”

To that end, she designed nanoparticles that deliver IL-12, a cytokine that stimulates nearby T cells to spring into action and begin attacking tumor cells. In a study of mice, she found that this treatment induced a long-term memory T-cell response that prevented recurrence of ovarian cancer.

Hammond closed her lecture by describing the impact that the Institute has had on her throughout her career.

“It’s been a transformative experience,” she said. “I really think of this place as special because it brings people together and enables us to do things together that we couldn’t do alone. And it is that support we get from our friends, our colleagues, and our students that really makes things possible.”

© Photo: Jake Belcher

Many vaccines, including vaccines for hepatitis B and whooping cough, consist of fragments of viral or bacterial proteins. These vaccines often include other molecules called adjuvants, which help to boost the immune system’s response to the protein.

Most of these adjuvants consist of aluminum salts or other molecules that provoke a nonspecific immune response. A team of MIT researchers has now shown that a type of nanoparticle called a metal organic framework (MOF) can also provoke a strong immune response, by activating the innate immune system — the body’s first line of defense against any pathogen — through cell proteins called toll-like receptors.

In a study of mice, the researchers showed that this MOF could successfully encapsulate and deliver part of the SARS-CoV-2 spike protein, while also acting as an adjuvant once the MOF is broken down inside cells.

While more work would be needed to adapt these particles for use as vaccines, the study demonstrates that this type of structure can be useful for generating a strong immune response, the researchers say.

“Understanding how the drug delivery vehicle can enhance an adjuvant immune response is something that could be very helpful in designing new vaccines,” says Ana Jaklenec, a principal investigator at MIT’s Koch Institute for Integrative Cancer Research and one of the senior authors of the new study.

Robert Langer, an MIT Institute Professor and member of the Koch Institute, and Dan Barouch, director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center and a professor at Harvard Medical School, are also senior authors of the paper, which appears today in Science Advances. The paper’s lead author is former MIT postdoc and Ibn Khaldun Fellow Shahad Alsaiari.

Immune activation

In this study, the researchers focused on a MOF called ZIF-8, which consists of a lattice of tetrahedral units made up of a zinc ion attached to four molecules of imidazole, an organic compound. Previous work has shown that ZIF-8 can significantly boost immune responses, but it wasn’t known exactly how this particle activates the immune system.

To try to figure that out, the MIT team created an experimental vaccine consisting of the SARS-CoV-2 receptor-binding protein (RBD) embedded within ZIF-8 particles. These particles are between 100 and 200 nanometers in diameter, a size that allows them to get into the body’s lymph nodes directly or through immune cells such as macrophages.

Once the particles enter the cells, the MOFs are broken down, releasing the viral proteins. The researchers found that the imidazole components then activate toll-like receptors (TLRs), which help to stimulate the innate immune response.

“This process is analogous to establishing a covert operative team at the molecular level to transport essential elements of the Covid-19 virus to the body’s immune system, where they can activate specific immune responses to boost vaccine efficacy,” Alsaiari says.

RNA sequencing of cells from the lymph nodes showed that mice vaccinated with ZIF-8 particles carrying the viral protein strongly activated a TLR pathway known as TLR-7, which led to greater production of cytokines and other molecules involved in inflammation.

Mice vaccinated with these particles generated a much stronger response to the viral protein than mice that received the protein on its own.

“Not only are we delivering the protein in a more controlled way through a nanoparticle, but the compositional structure of this particle is also acting as an adjuvant,” Jaklenec says. “We were able to achieve very specific responses to the Covid protein, and with a dose-sparing effect compared to using the protein by itself to vaccinate.”

Vaccine access

While this study and others have demonstrated ZIF-8’s immunogenic ability, more work needs to be done to evaluate the particles’ safety and potential to be scaled up for large-scale manufacturing. If ZIF-8 is not developed as a vaccine carrier, the findings from the study should help to guide researchers in developing similar nanoparticles that could be used to deliver subunit vaccines, Jaklenec says.

“Most subunit vaccines usually have two separate components: an antigen and an adjuvant,” Jaklenec says. “Designing new vaccines that utilize nanoparticles with specific chemical moieties which not only aid in antigen delivery but can also activate particular immune pathways have the potential to enhance vaccine potency.”

One advantage to developing a subunit vaccine for Covid-19 is that such vaccines are usually easier and cheaper to manufacture than mRNA vaccines, which could make it easier to distribute them around the world, the researchers say.

“Subunit vaccines have been around for a long time, and they tend to be cheaper to produce, so that opens up more access to vaccines, especially in times of pandemic,” Jaklenec says.

The research was funded by Ibn Khaldun Fellowships for Saudi Arabian Women and in part by the Koch Institute Support (core) Grant from the U.S. National Cancer Institute.

© Image: Courtesy of the researchers

A team of MIT researchers will lead a $65.67 million effort, awarded by the U.S. Advanced Research Projects Agency for Health (ARPA-H), to develop ingestible devices that may one day be used to treat diabetes, obesity, and other conditions through oral delivery of mRNA. Such devices could potentially be deployed for needle-free delivery of mRNA vaccines as well.

The five-year project also aims to develop electroceuticals, a new form of ingestible therapies based on electrical stimulation of the body’s own hormones and neural signaling. If successful, this approach could lead to new treatments for a variety of metabolic disorders.

“We know that the oral route is generally the preferred route of administration for both patients and health care providers,” says Giovanni Traverso, an associate professor of mechanical engineering at MIT and a gastroenterologist at Brigham and Women’s Hospital. “Our primary focus is on disorders of metabolism because they affect a lot of people, but the platforms we’re developing could be applied very broadly.”

Traverso is the principal investigator for the project, which also includes Robert Langer, MIT Institute Professor, and Anantha Chandrakasan, dean of the MIT School of Engineering and the Vannevar Bush Professor of Electrical Engineering and Computer Science. As part of the project, the MIT team will collaborate with investigators from Brigham and Women’s Hospital, New York University, and the University of Colorado School of Medicine.

Over the past several years, Traverso’s and Langer’s labs have designed many types of ingestible devices that can deliver drugs to the GI tract. This approach could be especially useful for protein drugs and nucleic acids, which typically can’t be given orally because they break down in the acidic environment of the digestive tract.

Messenger RNA has already proven useful as a vaccine, directing cells to produce fragments of viral proteins that trigger an immune response. Delivering mRNA to cells also holds potential to stimulate production of therapeutic molecules to treat a variety of diseases. In this project, the researchers plan to focus on metabolic diseases such as diabetes.

“What mRNA can do is enable the potential for dosing therapies that are very difficult to dose today, or provide longer-term coverage by essentially creating an internal factory that produces a therapy for a prolonged period,” Traverso says.

In the mRNA portion of the project, the research team intends to identify lipid and polymer nanoparticle formulations that can most effectively deliver mRNA to cells, using machine learning to help identify the best candidates. They will also develop and test ingestible devices to carry the mRNA-nanoparticle payload, with the goal of running a clinical trial in the final year of the five-year project.

The work will build on research that Traverso’s lab has already begun. In 2022, Traverso and his colleagues reported that they could deliver mRNA in capsules that inject mRNA-nanoparticle complexes into the lining of the stomach.

The other branch of the project will focus on ingestible devices that can deliver a small electrical current to the lining of the stomach. In a study published last year, Traverso’s lab demonstrated this approach for the first time, using a capsule coated with electrodes that apply an electrical current to cells of the stomach. In animal studies, they found that this stimulation boosted production of ghrelin, a hormone that stimulates appetite.

Traverso envisions that this type of treatment could potentially replace or complement some of the existing drugs used to prevent nausea and stimulate appetite in people with anorexia or cachexia (loss of body mass that can occur in patients with cancer or other chronic diseases). The researchers also hope to develop ways to stimulate production of GLP-1, a hormone that is used to help manage diabetes and promote weight loss.

“What this approach starts to do is potentially maximize our ability to treat disease without administering a new drug, but instead by simply modulating the body’s own systems through electrical stimulation,” Traverso says.

At MIT, Langer will help to develop nanoparticles for mRNA delivery, and Chandrakasan will work on ways to reduce energy consumption and miniaturize the electronic functions of the capsules, including secure communication, stimulation, and power generation.

The Brigham and Women’s Hospital’s portion of the project will be co-led by Traverso, Ameya Kirtane, Jason Li, and Peter Chai, who will amplify efforts on the formulation and stabilization of the mRNA nanoparticles, engineering of the ingestible devices, and running of clinical trials. At NYU, the effort will be led by assistant professor of bioengineering Khalil Ramadi SM ’16, PhD ’19, focusing on biological characterization of the effects of electrical stimulation. Researchers at the University of Colorado, led by Matthew Wynia and Eric G. Campbell of the CU Center for Bioethics and Humanities, will focus on exploring the ethical dimensions and public perceptions of these types of biomedical interventions.

“We felt like we had an opportunity here not only to do fundamental engineering science and early-stage clinical trials, but also to start to understand the data behind some of the ethical implications and public perceptions of these technologies through this broad collaboration,” Traverso says.

The project described here is supported by ARPA-H under award number D24AC00040-00. The content of this announcement does not necessarily represent the official views of the Advanced Research Projects Agency for Health.

© Image: Courtesy of MechE

Using a virus-like delivery particle made from DNA, researchers from MIT and the Ragon Institute of MGH, MIT, and Harvard have created a vaccine that can induce a strong antibody response against SARS-CoV-2.

The vaccine, which has been tested in mice, consists of a DNA scaffold that carries many copies of a viral antigen. This type of vaccine, known as a particulate vaccine, mimics the structure of a virus. Most previous work on particulate vaccines has relied on protein scaffolds, but the proteins used in those vaccines tend to generate an unnecessary immune response that can distract the immune system from the target.

In the mouse study, the researchers found that the DNA scaffold does not induce an immune response, allowing the immune system to focus its antibody response on the target antigen.

“DNA, we found in this work, does not elicit antibodies that may distract away from the protein of interest,” says Mark Bathe, an MIT professor of biological engineering. “What you can imagine is that your B cells and immune system are being fully trained by that target antigen, and that’s what you want — for your immune system to be laser-focused on the antigen of interest.”

This approach, which strongly stimulates B cells (the cells that produce antibodies), could make it easier to develop vaccines against viruses that have been difficult to target, including HIV and influenza, as well as SARS-CoV-2, the researchers say. Unlike T cells, which are stimulated by other types of vaccines, these B cells can persist for decades, offering long-term protection.

“We’re interested in exploring whether we can teach the immune system to deliver higher levels of immunity against pathogens that resist conventional vaccine approaches, like flu, HIV, and SARS-CoV-2,” says Daniel Lingwood, an associate professor at Harvard Medical School and a principal investigator at the Ragon Institute. “This idea of decoupling the response against the target antigen from the platform itself is a potentially powerful immunological trick that one can now bring to bear to help those immunological targeting decisions move in a direction that is more focused.”

Bathe, Lingwood, and Aaron Schmidt, an associate professor at Harvard Medical School and principal investigator at the Ragon Institute, are the senior authors of the paper, which appears today in Nature Communications. The paper’s lead authors are Eike-Christian Wamhoff, a former MIT postdoc; Larance Ronsard, a Ragon Institute postdoc; Jared Feldman, a former Harvard University graduate student; Grant Knappe, an MIT graduate student; and Blake Hauser, a former Harvard graduate student. 

Mimicking viruses

Particulate vaccines usually consist of a protein nanoparticle, similar in structure to a virus, that can carry many copies of a viral antigen. This high density of antigens can lead to a stronger immune response than traditional vaccines because the body sees it as similar to an actual virus. Particulate vaccines have been developed for a handful of pathogens, including hepatitis B and human papillomavirus, and a particulate vaccine for SARS-CoV-2 has been approved for use in South Korea.

These vaccines are especially good at activating B cells, which produce antibodies specific to the vaccine antigen.

“Particulate vaccines are of great interest for many in immunology because they give you robust humoral immunity, which is antibody-based immunity, which is differentiated from the T-cell-based immunity that the mRNA vaccines seem to elicit more strongly,” Bathe says.

A potential drawback to this kind of vaccine, however, is that the proteins used for the scaffold often stimulate the body to produce antibodies targeting the scaffold. This can distract the immune system and prevent it from launching as robust a response as one would like, Bathe says.

“To neutralize the SARS-CoV-2 virus, you want to have a vaccine that generates antibodies toward the receptor binding domain portion of the virus’ spike protein,” he says. “When you display that on a protein-based particle, what happens is your immune system recognizes not only that receptor binding domain protein, but all the other proteins that are irrelevant to the immune response you’re trying to elicit.”

Another potential drawback is that if the same person receives more than one vaccine carried by the same protein scaffold, for example, SARS-CoV-2 and then influenza, their immune system would likely respond right away to the protein scaffold, having already been primed to react to it. This could weaken the immune response to the antigen carried by the second vaccine.

“If you want to apply that protein-based particle to immunize against a different virus like influenza, then your immune system can be addicted to the underlying protein scaffold that it’s already seen and developed an immune response toward,” Bathe says. “That can hypothetically diminish the quality of your antibody response for the actual antigen of interest.”

As an alternative, Bathe’s lab has been developing scaffolds made using DNA origami, a method that offers precise control over the structure of synthetic DNA and allows researchers to attach a variety of molecules, such as viral antigens, at specific locations.

In a 2020 study, Bathe and Darrell Irvine, an MIT professor of biological engineering and of materials science and engineering, showed that a DNA scaffold carrying 30 copies of an HIV antigen could generate a strong antibody response in B cells grown in the lab. This type of structure is optimal for activating B cells because it closely mimics the structure of nano-sized viruses, which display many copies of viral proteins in their surfaces.

“This approach builds off of a fundamental principle in B-cell antigen recognition, which is that if you have an arrayed display of the antigen, that promotes B-cell responses and gives better quantity and quality of antibody output,” Lingwood says.

“Immunologically silent”

In the new study, the researchers swapped in an antigen consisting of the receptor binding protein of the spike protein from the original strain of SARS-CoV-2. When they gave the vaccine to mice, they found that the mice generated high levels of antibodies to the spike protein but did not generate any to the DNA scaffold.

In contrast, a vaccine based on a scaffold protein called ferritin, coated with SARS-CoV-2 antigens, generated many antibodies against ferritin as well as SARS-CoV-2.

“The DNA nanoparticle itself is immunogenically silent,” Lingwood says. “If you use a protein-based platform, you get equally high titer antibody responses to the platform and to the antigen of interest, and that can complicate repeated usage of that platform because you’ll develop high affinity immune memory against it.”

Reducing these off-target effects could also help scientists reach the goal of developing a vaccine that would induce broadly neutralizing antibodies to any variant of SARS-CoV-2, or even to all sarbecoviruses, the subgenus of virus that includes SARS-CoV-2 as well as the viruses that cause SARS and MERS.

To that end, the researchers are now exploring whether a DNA scaffold with many different viral antigens attached could induce broadly neutralizing antibodies against SARS-CoV-2 and related viruses. 

The research was primarily funded by the National Institutes of Health, the National Science Foundation, and the Fast Grants program.

© Credit: The Bathe Lab

Tumors constantly shed DNA from dying cells, which briefly circulates in the patient’s bloodstream before it is quickly broken down. Many companies have created blood tests that can pick out this tumor DNA, potentially helping doctors diagnose or monitor cancer or choose a treatment.

The amount of tumor DNA circulating at any given time, however, is extremely small, so it has been challenging to develop tests sensitive enough to pick up that tiny signal. A team of researchers from MIT and the Broad Institute of MIT and Harvard has now come up with a way to significantly boost that signal, by temporarily slowing the clearance of tumor DNA circulating in the bloodstream.

The researchers developed two different types of injectable molecules that they call “priming agents,” which can transiently interfere with the body’s ability to remove circulating tumor DNA from the bloodstream. In a study of mice, they showed that these agents could boost DNA levels enough that the percentage of detectable early-stage lung metastases leapt from less than 10 percent to above 75 percent.

This approach could enable not only earlier diagnosis of cancer, but also more sensitive detection of tumor mutations that could be used to guide treatment. It could also help improve detection of cancer recurrence.

“You can give one of these agents an hour before the blood draw, and it makes things visible that previously wouldn’t have been. The implication is that we should be able to give everybody who’s doing liquid biopsies, for any purpose, more molecules to work with,” says Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and of Electrical Engineering and Computer Science at MIT, and a member of MIT’s Koch Institute for Integrative Cancer Research and the Institute for Medical Engineering and Science.

Bhatia is one of the senior authors of the new study, along with J. Christopher Love, the Raymond A. and Helen E. St. Laurent Professor of Chemical Engineering at MIT and a member of the Koch Institute and the Ragon Institute of MGH, MIT, and Harvard and Viktor Adalsteinsson, director of the Gerstner Center for Cancer Diagnostics at the Broad Institute.

Carmen Martin-Alonso PhD ’23, MIT and Broad Institute postdoc Shervin Tabrizi, and Broad Institute scientist Kan Xiong are the lead authors of the paper, which appears today in Science.

Better biopsies

Liquid biopsies, which enable detection of small quantities of DNA in blood samples, are now used in many cancer patients to identify mutations that could help guide treatment. With greater sensitivity, however, these tests could become useful for far more patients. Most efforts to improve the sensitivity of liquid biopsies have focused on developing new sequencing technologies to use after the blood is drawn.

While brainstorming ways to make liquid biopsies more informative, Bhatia, Love, Adalsteinsson, and their trainees came up with the idea of trying to increase the amount of DNA in a patient’s bloodstream before the sample is taken.

“A tumor is always creating new cell-free DNA, and that’s the signal that we’re attempting to detect in the blood draw. Existing liquid biopsy technologies, however, are limited by the amount of material you collect in the tube of blood,” Love says. “Where this work intercedes is thinking about how to inject something beforehand that would help boost or enhance the amount of signal that is available to collect in the same small sample.”

The body uses two primary strategies to remove circulating DNA from the bloodstream. Enzymes called DNases circulate in the blood and break down DNA that they encounter, while immune cells known as macrophages take up cell-free DNA as blood is filtered through the liver.

The researchers decided to target each of these processes separately. To prevent DNases from breaking down DNA, they designed a monoclonal antibody that binds to circulating DNA and protects it from the enzymes.

“Antibodies are well-established biopharmaceutical modalities, and they’re safe in a number of different disease contexts, including cancer and autoimmune treatments,” Love says. “The idea was, could we use this kind of antibody to help shield the DNA temporarily from degradation by the nucleases that are in circulation? And by doing so, we shift the balance to where the tumor is generating DNA slightly faster than is being degraded, increasing the concentration in a blood draw.”

The other priming agent they developed is a nanoparticle designed to block macrophages from taking up cell-free DNA. These cells have a well-known tendency to eat up synthetic nanoparticles.

“DNA is a biological nanoparticle, and it made sense that immune cells in the liver were probably taking this up just like they do synthetic nanoparticles. And if that were the case, which it turned out to be, then we could use a safe dummy nanoparticle to distract those immune cells and leave the circulating DNA alone so that it could be at a higher concentration,” Bhatia says.

Earlier tumor detection

The researchers tested their priming agents in mice that received transplants of cancer cells that tend to form tumors in the lungs. Two weeks after the cells were transplanted, the researchers showed that these priming agents could boost the amount of circulating tumor DNA recovered in a blood sample by up to 60-fold.

Once the blood sample is taken, it can be run through the same kinds of sequencing tests now used on liquid biopsy samples. These tests can pick out tumor DNA, including specific sequences used to determine the type of tumor and potentially what kinds of treatments would work best.

Early detection of cancer is another promising application for these priming agents. The researchers found that when mice were given the nanoparticle priming agent before blood was drawn, it allowed them to detect circulating tumor DNA in blood of 75 percent of the mice with low cancer burden, while none were detectable without this boost.

“One of the greatest hurdles for cancer liquid biopsy testing has been the scarcity of circulating tumor DNA in a blood sample,” Adalsteinsson says. “It’s thus been encouraging to see the magnitude of the effect we’ve been able to achieve so far and to envision what impact this could have for patients.”

After either of the priming agents are injected, it takes an hour or two for the DNA levels to increase in the bloodstream, and then they return to normal within about 24 hours.

“The ability to get peak activity of these agents within a couple of hours, followed by their rapid clearance, means that someone could go into a doctor’s office, receive an agent like this, and then give their blood for the test itself, all within one visit,” Love says. “This feature bodes well for the potential to translate this concept into clinical use.”

The researchers have launched a company called Amplifyer Bio that plans to further develop the technology, in hopes of advancing to clinical trials.

“A tube of blood is a much more accessible diagnostic than colonoscopy screening or even mammography,” Bhatia says. “Ultimately, if these tools really are predictive, then we should be able to get many more patients into the system who could benefit from cancer interception or better therapy.”

The research was funded by the Koch Institute Support (core) Grant from the National Cancer Institute, the Marble Center for Cancer Nanomedicine, the Gerstner Family Foundation, the Ludwig Center at MIT, the Koch Institute Frontier Research Program via the Casey and Family Foundation, and the Bridge Project, a partnership between the Koch Institute and the Dana-Farber/Harvard Cancer Center.

© Image: MIT News; iStock

An MIT research team led by Professor Darrell Irvine has developed a novel kind of vaccine adjuvant: a nanoparticle that can help to stimulate the immune system to generate a stronger response to a vaccine. These nanoparticles contain saponin, a compound derived from the bark of the Chilean soapbark tree, along with a molecule called MPLA, each of which helps to activate the immune system.

The adjuvant has been incorporated into an experimental HIV vaccine that has shown promising results in animal studies, and this month, the first human volunteers will receive the vaccine as part of a phase 1 clinical trial run by the Consortium for HIV/AIDS Vaccine Development at the Scripps Research Institute. MIT News spoke with Irvine about why this project required an interdisciplinary approach, and what may lie ahead.

Q: What are the special features of the new nanoparticle adjuvant that help it create a more powerful immune response to vaccination? 

A: Most vaccines, such as the Covid-19 vaccines, are thought to protect us through B cells making protective antibodies. Development of an HIV vaccine has been made challenging by the fact that the B cells that are capable of evolving to produce protective antibodies — called broadly neutralizing antibodies — are very rare in the average person. Vaccine adjuvants are important in this scenario to ensure that when we immunize with an HIV antigen, these rare B cells become activated and get a chance to participate in the immune response.

We particularly discovered that this new adjuvant, which we call SMNP (short for saponin/MPLA nanoparticles), is particularly good at helping more B cells enter germinal centers, the specialized location in lymph nodes where high affinity antibodies are produced. In animal models, SMNP also has shown unique mechanisms of action: Administering antigens with SMNP leads to better antigen delivery to lymph nodes (through increases in lymph flow) and better capture of the antigen by B cells in lymph nodes.

Q: How did your lab, which generally focuses on bioengineering and materials science, end up working on HIV vaccines? What obstacles did you have to overcome in the development of this adjuvant?

A: About 15 years ago, Bruce Walker approached me about getting involved in the HIV vaccine effort, and recruited me to join the Ragon Institute of MGH, MIT, and Harvard as a member of the steering committee. Through the Ragon Institute, I met colleagues in the Scripps Consortium for HIV/AIDS Vaccine Development (CHAVD), and we realized there was a tremendous opportunity to directly contribute to the HIV vaccine challenge, working in partnership with experts in immunogen design, structural biology, and HIV pathogenesis.

As we carried out study after study of SMNP in preclinical animal models, we realized the adjuvant had really amazing effects for promoting anti-HIV antibody responses, and the CHAVD decided this was worth moving forward to testing in humans. A major challenge was transferring the technology out of the lab to synthesize large amounts of the adjuvant under GMP (good manufacturing process) conditions for a clinical trial. The initial contract manufacturing organization (CMO) hired by the consortium to produce SMNP simply couldn’t get a process to work for scalable manufacturing.

Luckily for us, a chemical engineering graduate student, Ivan Pires, whom I co-advise with Paula Hammond, head of MIT’s Department of Chemical Engineering, had developed expertise in one particular processing technique known as tangential flow filtration during his undergraduate training. Leveraging classic chemical engineering skills in thermodynamics and process design, Ivan stepped in and solved the process issues the CMO was facing, allowing the manufacturing to move forward. This to me is what makes MIT great — the ability of our students and postdocs to step up and solve big problems and make big contributions when the need arises.

Q: What other diseases could this approach be useful for? Are there any plans to test it with other types of vaccines?

A: In principle, SMNP may be helpful for any infectious disease vaccine where strong antibody responses are needed. We are currently sharing the adjuvant with about 30 different labs around the world, who are testing it in vaccines against many other pathogens including Epstein-Barr virus, malaria, and influenza. We are hopeful that if SMNP is safe and effective in humans, this will be an adjuvant that can be broadly used in infectious disease trials.

© Photo: Steve Boxall

When Paula Hammond first arrived on MIT’s campus as a first-year student in the early 1980s, she wasn’t sure if she belonged. In fact, as she told an MIT audience yesterday, she felt like “an imposter.”

However, that feeling didn’t last long, as Hammond began to find support among her fellow students and MIT’s faculty. “Community was really important for me, to feel that I belonged, to feel that I had a place here, and I found people who were willing to embrace me and support me,” she said.

Hammond, a world-renowned chemical engineer who has spent most of her academic career at MIT, made her remarks during the 2023-24 James R. Killian Jr. Faculty Achievement Award lecture.

Established in 1971 to honor MIT’s 10th president, James Killian, the Killian Award recognizes extraordinary professional achievements by an MIT faculty member. Hammond was chosen for this year’s award “not only for her tremendous professional achievements and contributions, but also for her genuine warmth and humanity, her thoughtfulness and effective leadership, and her empathy and ethics,” according to the award citation.

“Professor Hammond is a pioneer in nanotechnology research. With a program that extends from basic science to translational research in medicine and energy, she has introduced new approaches for the design and development of complex drug delivery systems for cancer treatment and noninvasive imaging,” said Mary Fuller, chair of MIT’s faculty and a professor of literature, who presented the award. “As her colleagues, we are delighted to celebrate her career today.”

In January, Hammond began serving as MIT’s vice provost for faculty. Before that, she chaired the Department of Chemical Engineering for eight years, and she was named an Institute Professor in 2021.

A versatile technique

Hammond, who grew up in Detroit, credits her parents with instilling a love of science. Her father was one of very few Black PhDs in biochemistry at the time, while her mother earned a master’s degree in nursing from Howard University and founded the nursing school at Wayne County Community College. “That provided a huge amount of opportunity for women in the area of Detroit, including women of color,” Hammond noted.

After earning her bachelor’s degree from MIT in 1984, Hammond worked as an engineer before returning to the Institute as a graduate student, earning her PhD in 1993. After a two-year postdoc at Harvard University, she returned to join the MIT faculty in 1995.

At the heart of Hammond’s research is a technique she developed to create thin films that can essentially “shrink-wrap” nanoparticles. By tuning the chemical composition of these films, the particles can be customized to deliver drugs or nucleic acids and to target specific cells in the body, including cancer cells.

To make these films, Hammond begins by layering positively charged polymers onto a negatively charged surface. Then, more layers can be added, alternating positively and negatively charged polymers. Each of these layers may contain drugs or other useful molecules, such as DNA or RNA. Some of these films contain hundreds of layers, others just one, making them useful for a wide range of applications.

“What’s nice about the layer-by-layer process is I can choose a group of degradable polymers that are nicely biocompatible, and I can alternate them with our drug materials. This means that I can build up thin film layers that contain different drugs at different points within the film,” Hammond said. “Then, when the film degrades, it can release those drugs in reverse order. This is enabling us to create complex, multidrug films, using a simple water-based technique.”

Hammond described how these layer-by-layer films can be used to promote bone growth, in an application that could help people born with congenital bone defects or people who experience traumatic injuries.

For that use, her lab has created films with layers of two proteins. One of these, BMP-2, is a protein that interacts with adult stem cells and induces them to differentiate into bone cells, generating new bone. The second is a growth factor called VEGF, which stimulates the growth of new blood vessels that help bone to regenerate. These layers are applied to a very thin tissue scaffold that can be implanted at the injury site.

Hammond and her students designed the coating so that once implanted, it would release VEGF early, over a week or so, and continue releasing BMP-2 for up to 40 days. In a study of mice, they found that this tissue scaffold stimulated the growth of new bone that was nearly indistinguishable from natural bone.

Targeting cancer

As a member of MIT’s Koch Institute for Integrative Cancer Research, Hammond has also developed layer-by-layer coatings that can improve the performance of nanoparticles used for cancer drug delivery, such as liposomes or nanoparticles made from a polymer called PLGA.

“We have a broad range of drug carriers that we can wrap this way. I think of them like a gobstopper, where there are all those different layers of candy and they dissolve one at a time,” Hammond said.

Using this approach, Hammond has created particles that can deliver a one-two punch to cancer cells. First, the particles release a dose of a nucleic acid such as short interfering RNA (siRNA), which can turn off a cancerous gene, or microRNA, which can activate tumor suppressor genes. Then, the particles release a chemotherapy drug such as cisplatin, to which the cells are now more vulnerable.

The particles also include a negatively charged outer “stealth layer” that protects them from being broken down in the bloodstream before they can reach their targets. This outer layer can also be modified to help the particles get taken up by cancer cells, by incorporating molecules that bind to proteins that are abundant on tumor cells.

In more recent work, Hammond has begun developing nanoparticles that can target ovarian cancer and help prevent recurrence of the disease after chemotherapy. In about 70 percent of ovarian cancer patients, the first round of treatment is highly effective, but tumors recur in about 85 percent of those cases, and these new tumors are usually highly drug resistant.

By altering the type of coating applied to drug-delivering nanoparticles, Hammond has found that the particles can be designed to either get inside tumor cells or stick to their surfaces. Using particles that stick to the cells, she has designed a treatment that could help to jumpstart a patient’s immune response to any recurrent tumor cells.

“With ovarian cancer, very few immune cells exist in that space, and because they don’t have a lot of immune cells present, it’s very difficult to rev up an immune response,” she said. “However, if we can deliver a molecule to neighboring cells, those few that are present, and get them revved up, then we might be able to do something.”

To that end, she designed nanoparticles that deliver IL-12, a cytokine that stimulates nearby T cells to spring into action and begin attacking tumor cells. In a study of mice, she found that this treatment induced a long-term memory T-cell response that prevented recurrence of ovarian cancer.

Hammond closed her lecture by describing the impact that the Institute has had on her throughout her career.

“It’s been a transformative experience,” she said. “I really think of this place as special because it brings people together and enables us to do things together that we couldn’t do alone. And it is that support we get from our friends, our colleagues, and our students that really makes things possible.”

© Photo: Jake Belcher

Many vaccines, including vaccines for hepatitis B and whooping cough, consist of fragments of viral or bacterial proteins. These vaccines often include other molecules called adjuvants, which help to boost the immune system’s response to the protein.

Most of these adjuvants consist of aluminum salts or other molecules that provoke a nonspecific immune response. A team of MIT researchers has now shown that a type of nanoparticle called a metal organic framework (MOF) can also provoke a strong immune response, by activating the innate immune system — the body’s first line of defense against any pathogen — through cell proteins called toll-like receptors.

In a study of mice, the researchers showed that this MOF could successfully encapsulate and deliver part of the SARS-CoV-2 spike protein, while also acting as an adjuvant once the MOF is broken down inside cells.

While more work would be needed to adapt these particles for use as vaccines, the study demonstrates that this type of structure can be useful for generating a strong immune response, the researchers say.

“Understanding how the drug delivery vehicle can enhance an adjuvant immune response is something that could be very helpful in designing new vaccines,” says Ana Jaklenec, a principal investigator at MIT’s Koch Institute for Integrative Cancer Research and one of the senior authors of the new study.

Robert Langer, an MIT Institute Professor and member of the Koch Institute, and Dan Barouch, director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center and a professor at Harvard Medical School, are also senior authors of the paper, which appears today in Science Advances. The paper’s lead author is former MIT postdoc and Ibn Khaldun Fellow Shahad Alsaiari.

Immune activation

In this study, the researchers focused on a MOF called ZIF-8, which consists of a lattice of tetrahedral units made up of a zinc ion attached to four molecules of imidazole, an organic compound. Previous work has shown that ZIF-8 can significantly boost immune responses, but it wasn’t known exactly how this particle activates the immune system.

To try to figure that out, the MIT team created an experimental vaccine consisting of the SARS-CoV-2 receptor-binding protein (RBD) embedded within ZIF-8 particles. These particles are between 100 and 200 nanometers in diameter, a size that allows them to get into the body’s lymph nodes directly or through immune cells such as macrophages.

Once the particles enter the cells, the MOFs are broken down, releasing the viral proteins. The researchers found that the imidazole components then activate toll-like receptors (TLRs), which help to stimulate the innate immune response.

“This process is analogous to establishing a covert operative team at the molecular level to transport essential elements of the Covid-19 virus to the body’s immune system, where they can activate specific immune responses to boost vaccine efficacy,” Alsaiari says.

RNA sequencing of cells from the lymph nodes showed that mice vaccinated with ZIF-8 particles carrying the viral protein strongly activated a TLR pathway known as TLR-7, which led to greater production of cytokines and other molecules involved in inflammation.

Mice vaccinated with these particles generated a much stronger response to the viral protein than mice that received the protein on its own.

“Not only are we delivering the protein in a more controlled way through a nanoparticle, but the compositional structure of this particle is also acting as an adjuvant,” Jaklenec says. “We were able to achieve very specific responses to the Covid protein, and with a dose-sparing effect compared to using the protein by itself to vaccinate.”

Vaccine access

While this study and others have demonstrated ZIF-8’s immunogenic ability, more work needs to be done to evaluate the particles’ safety and potential to be scaled up for large-scale manufacturing. If ZIF-8 is not developed as a vaccine carrier, the findings from the study should help to guide researchers in developing similar nanoparticles that could be used to deliver subunit vaccines, Jaklenec says.

“Most subunit vaccines usually have two separate components: an antigen and an adjuvant,” Jaklenec says. “Designing new vaccines that utilize nanoparticles with specific chemical moieties which not only aid in antigen delivery but can also activate particular immune pathways have the potential to enhance vaccine potency.”

One advantage to developing a subunit vaccine for Covid-19 is that such vaccines are usually easier and cheaper to manufacture than mRNA vaccines, which could make it easier to distribute them around the world, the researchers say.

“Subunit vaccines have been around for a long time, and they tend to be cheaper to produce, so that opens up more access to vaccines, especially in times of pandemic,” Jaklenec says.

The research was funded by Ibn Khaldun Fellowships for Saudi Arabian Women and in part by the Koch Institute Support (core) Grant from the U.S. National Cancer Institute.

© Image: Courtesy of the researchers

A team of MIT researchers will lead a $65.67 million effort, awarded by the U.S. Advanced Research Projects Agency for Health (ARPA-H), to develop ingestible devices that may one day be used to treat diabetes, obesity, and other conditions through oral delivery of mRNA. Such devices could potentially be deployed for needle-free delivery of mRNA vaccines as well.

The five-year project also aims to develop electroceuticals, a new form of ingestible therapies based on electrical stimulation of the body’s own hormones and neural signaling. If successful, this approach could lead to new treatments for a variety of metabolic disorders.

“We know that the oral route is generally the preferred route of administration for both patients and health care providers,” says Giovanni Traverso, an associate professor of mechanical engineering at MIT and a gastroenterologist at Brigham and Women’s Hospital. “Our primary focus is on disorders of metabolism because they affect a lot of people, but the platforms we’re developing could be applied very broadly.”

Traverso is the principal investigator for the project, which also includes Robert Langer, MIT Institute Professor, and Anantha Chandrakasan, dean of the MIT School of Engineering and the Vannevar Bush Professor of Electrical Engineering and Computer Science. As part of the project, the MIT team will collaborate with investigators from Brigham and Women’s Hospital, New York University, and the University of Colorado School of Medicine.

Over the past several years, Traverso’s and Langer’s labs have designed many types of ingestible devices that can deliver drugs to the GI tract. This approach could be especially useful for protein drugs and nucleic acids, which typically can’t be given orally because they break down in the acidic environment of the digestive tract.

Messenger RNA has already proven useful as a vaccine, directing cells to produce fragments of viral proteins that trigger an immune response. Delivering mRNA to cells also holds potential to stimulate production of therapeutic molecules to treat a variety of diseases. In this project, the researchers plan to focus on metabolic diseases such as diabetes.

“What mRNA can do is enable the potential for dosing therapies that are very difficult to dose today, or provide longer-term coverage by essentially creating an internal factory that produces a therapy for a prolonged period,” Traverso says.

In the mRNA portion of the project, the research team intends to identify lipid and polymer nanoparticle formulations that can most effectively deliver mRNA to cells, using machine learning to help identify the best candidates. They will also develop and test ingestible devices to carry the mRNA-nanoparticle payload, with the goal of running a clinical trial in the final year of the five-year project.

The work will build on research that Traverso’s lab has already begun. In 2022, Traverso and his colleagues reported that they could deliver mRNA in capsules that inject mRNA-nanoparticle complexes into the lining of the stomach.

The other branch of the project will focus on ingestible devices that can deliver a small electrical current to the lining of the stomach. In a study published last year, Traverso’s lab demonstrated this approach for the first time, using a capsule coated with electrodes that apply an electrical current to cells of the stomach. In animal studies, they found that this stimulation boosted production of ghrelin, a hormone that stimulates appetite.

Traverso envisions that this type of treatment could potentially replace or complement some of the existing drugs used to prevent nausea and stimulate appetite in people with anorexia or cachexia (loss of body mass that can occur in patients with cancer or other chronic diseases). The researchers also hope to develop ways to stimulate production of GLP-1, a hormone that is used to help manage diabetes and promote weight loss.

“What this approach starts to do is potentially maximize our ability to treat disease without administering a new drug, but instead by simply modulating the body’s own systems through electrical stimulation,” Traverso says.

At MIT, Langer will help to develop nanoparticles for mRNA delivery, and Chandrakasan will work on ways to reduce energy consumption and miniaturize the electronic functions of the capsules, including secure communication, stimulation, and power generation.

The Brigham and Women’s Hospital’s portion of the project will be co-led by Traverso, Ameya Kirtane, Jason Li, and Peter Chai, who will amplify efforts on the formulation and stabilization of the mRNA nanoparticles, engineering of the ingestible devices, and running of clinical trials. At NYU, the effort will be led by assistant professor of bioengineering Khalil Ramadi SM ’16, PhD ’19, focusing on biological characterization of the effects of electrical stimulation. Researchers at the University of Colorado, led by Matthew Wynia and Eric G. Campbell of the CU Center for Bioethics and Humanities, will focus on exploring the ethical dimensions and public perceptions of these types of biomedical interventions.

“We felt like we had an opportunity here not only to do fundamental engineering science and early-stage clinical trials, but also to start to understand the data behind some of the ethical implications and public perceptions of these technologies through this broad collaboration,” Traverso says.

The project described here is supported by ARPA-H under award number D24AC00040-00. The content of this announcement does not necessarily represent the official views of the Advanced Research Projects Agency for Health.

© Image: Courtesy of MechE

Using a virus-like delivery particle made from DNA, researchers from MIT and the Ragon Institute of MGH, MIT, and Harvard have created a vaccine that can induce a strong antibody response against SARS-CoV-2.

The vaccine, which has been tested in mice, consists of a DNA scaffold that carries many copies of a viral antigen. This type of vaccine, known as a particulate vaccine, mimics the structure of a virus. Most previous work on particulate vaccines has relied on protein scaffolds, but the proteins used in those vaccines tend to generate an unnecessary immune response that can distract the immune system from the target.

In the mouse study, the researchers found that the DNA scaffold does not induce an immune response, allowing the immune system to focus its antibody response on the target antigen.

“DNA, we found in this work, does not elicit antibodies that may distract away from the protein of interest,” says Mark Bathe, an MIT professor of biological engineering. “What you can imagine is that your B cells and immune system are being fully trained by that target antigen, and that’s what you want — for your immune system to be laser-focused on the antigen of interest.”

This approach, which strongly stimulates B cells (the cells that produce antibodies), could make it easier to develop vaccines against viruses that have been difficult to target, including HIV and influenza, as well as SARS-CoV-2, the researchers say. Unlike T cells, which are stimulated by other types of vaccines, these B cells can persist for decades, offering long-term protection.

“We’re interested in exploring whether we can teach the immune system to deliver higher levels of immunity against pathogens that resist conventional vaccine approaches, like flu, HIV, and SARS-CoV-2,” says Daniel Lingwood, an associate professor at Harvard Medical School and a principal investigator at the Ragon Institute. “This idea of decoupling the response against the target antigen from the platform itself is a potentially powerful immunological trick that one can now bring to bear to help those immunological targeting decisions move in a direction that is more focused.”

Bathe, Lingwood, and Aaron Schmidt, an associate professor at Harvard Medical School and principal investigator at the Ragon Institute, are the senior authors of the paper, which appears today in Nature Communications. The paper’s lead authors are Eike-Christian Wamhoff, a former MIT postdoc; Larance Ronsard, a Ragon Institute postdoc; Jared Feldman, a former Harvard University graduate student; Grant Knappe, an MIT graduate student; and Blake Hauser, a former Harvard graduate student. 

Mimicking viruses

Particulate vaccines usually consist of a protein nanoparticle, similar in structure to a virus, that can carry many copies of a viral antigen. This high density of antigens can lead to a stronger immune response than traditional vaccines because the body sees it as similar to an actual virus. Particulate vaccines have been developed for a handful of pathogens, including hepatitis B and human papillomavirus, and a particulate vaccine for SARS-CoV-2 has been approved for use in South Korea.

These vaccines are especially good at activating B cells, which produce antibodies specific to the vaccine antigen.

“Particulate vaccines are of great interest for many in immunology because they give you robust humoral immunity, which is antibody-based immunity, which is differentiated from the T-cell-based immunity that the mRNA vaccines seem to elicit more strongly,” Bathe says.

A potential drawback to this kind of vaccine, however, is that the proteins used for the scaffold often stimulate the body to produce antibodies targeting the scaffold. This can distract the immune system and prevent it from launching as robust a response as one would like, Bathe says.

“To neutralize the SARS-CoV-2 virus, you want to have a vaccine that generates antibodies toward the receptor binding domain portion of the virus’ spike protein,” he says. “When you display that on a protein-based particle, what happens is your immune system recognizes not only that receptor binding domain protein, but all the other proteins that are irrelevant to the immune response you’re trying to elicit.”

Another potential drawback is that if the same person receives more than one vaccine carried by the same protein scaffold, for example, SARS-CoV-2 and then influenza, their immune system would likely respond right away to the protein scaffold, having already been primed to react to it. This could weaken the immune response to the antigen carried by the second vaccine.

“If you want to apply that protein-based particle to immunize against a different virus like influenza, then your immune system can be addicted to the underlying protein scaffold that it’s already seen and developed an immune response toward,” Bathe says. “That can hypothetically diminish the quality of your antibody response for the actual antigen of interest.”

As an alternative, Bathe’s lab has been developing scaffolds made using DNA origami, a method that offers precise control over the structure of synthetic DNA and allows researchers to attach a variety of molecules, such as viral antigens, at specific locations.

In a 2020 study, Bathe and Darrell Irvine, an MIT professor of biological engineering and of materials science and engineering, showed that a DNA scaffold carrying 30 copies of an HIV antigen could generate a strong antibody response in B cells grown in the lab. This type of structure is optimal for activating B cells because it closely mimics the structure of nano-sized viruses, which display many copies of viral proteins in their surfaces.

“This approach builds off of a fundamental principle in B-cell antigen recognition, which is that if you have an arrayed display of the antigen, that promotes B-cell responses and gives better quantity and quality of antibody output,” Lingwood says.

“Immunologically silent”

In the new study, the researchers swapped in an antigen consisting of the receptor binding protein of the spike protein from the original strain of SARS-CoV-2. When they gave the vaccine to mice, they found that the mice generated high levels of antibodies to the spike protein but did not generate any to the DNA scaffold.

In contrast, a vaccine based on a scaffold protein called ferritin, coated with SARS-CoV-2 antigens, generated many antibodies against ferritin as well as SARS-CoV-2.

“The DNA nanoparticle itself is immunogenically silent,” Lingwood says. “If you use a protein-based platform, you get equally high titer antibody responses to the platform and to the antigen of interest, and that can complicate repeated usage of that platform because you’ll develop high affinity immune memory against it.”

Reducing these off-target effects could also help scientists reach the goal of developing a vaccine that would induce broadly neutralizing antibodies to any variant of SARS-CoV-2, or even to all sarbecoviruses, the subgenus of virus that includes SARS-CoV-2 as well as the viruses that cause SARS and MERS.

To that end, the researchers are now exploring whether a DNA scaffold with many different viral antigens attached could induce broadly neutralizing antibodies against SARS-CoV-2 and related viruses. 

The research was primarily funded by the National Institutes of Health, the National Science Foundation, and the Fast Grants program.

© Credit: The Bathe Lab

Tumors constantly shed DNA from dying cells, which briefly circulates in the patient’s bloodstream before it is quickly broken down. Many companies have created blood tests that can pick out this tumor DNA, potentially helping doctors diagnose or monitor cancer or choose a treatment.

The amount of tumor DNA circulating at any given time, however, is extremely small, so it has been challenging to develop tests sensitive enough to pick up that tiny signal. A team of researchers from MIT and the Broad Institute of MIT and Harvard has now come up with a way to significantly boost that signal, by temporarily slowing the clearance of tumor DNA circulating in the bloodstream.

The researchers developed two different types of injectable molecules that they call “priming agents,” which can transiently interfere with the body’s ability to remove circulating tumor DNA from the bloodstream. In a study of mice, they showed that these agents could boost DNA levels enough that the percentage of detectable early-stage lung metastases leapt from less than 10 percent to above 75 percent.

This approach could enable not only earlier diagnosis of cancer, but also more sensitive detection of tumor mutations that could be used to guide treatment. It could also help improve detection of cancer recurrence.

“You can give one of these agents an hour before the blood draw, and it makes things visible that previously wouldn’t have been. The implication is that we should be able to give everybody who’s doing liquid biopsies, for any purpose, more molecules to work with,” says Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and of Electrical Engineering and Computer Science at MIT, and a member of MIT’s Koch Institute for Integrative Cancer Research and the Institute for Medical Engineering and Science.

Bhatia is one of the senior authors of the new study, along with J. Christopher Love, the Raymond A. and Helen E. St. Laurent Professor of Chemical Engineering at MIT and a member of the Koch Institute and the Ragon Institute of MGH, MIT, and Harvard and Viktor Adalsteinsson, director of the Gerstner Center for Cancer Diagnostics at the Broad Institute.

Carmen Martin-Alonso PhD ’23, MIT and Broad Institute postdoc Shervin Tabrizi, and Broad Institute scientist Kan Xiong are the lead authors of the paper, which appears today in Science.

Better biopsies

Liquid biopsies, which enable detection of small quantities of DNA in blood samples, are now used in many cancer patients to identify mutations that could help guide treatment. With greater sensitivity, however, these tests could become useful for far more patients. Most efforts to improve the sensitivity of liquid biopsies have focused on developing new sequencing technologies to use after the blood is drawn.

While brainstorming ways to make liquid biopsies more informative, Bhatia, Love, Adalsteinsson, and their trainees came up with the idea of trying to increase the amount of DNA in a patient’s bloodstream before the sample is taken.

“A tumor is always creating new cell-free DNA, and that’s the signal that we’re attempting to detect in the blood draw. Existing liquid biopsy technologies, however, are limited by the amount of material you collect in the tube of blood,” Love says. “Where this work intercedes is thinking about how to inject something beforehand that would help boost or enhance the amount of signal that is available to collect in the same small sample.”

The body uses two primary strategies to remove circulating DNA from the bloodstream. Enzymes called DNases circulate in the blood and break down DNA that they encounter, while immune cells known as macrophages take up cell-free DNA as blood is filtered through the liver.

The researchers decided to target each of these processes separately. To prevent DNases from breaking down DNA, they designed a monoclonal antibody that binds to circulating DNA and protects it from the enzymes.

“Antibodies are well-established biopharmaceutical modalities, and they’re safe in a number of different disease contexts, including cancer and autoimmune treatments,” Love says. “The idea was, could we use this kind of antibody to help shield the DNA temporarily from degradation by the nucleases that are in circulation? And by doing so, we shift the balance to where the tumor is generating DNA slightly faster than is being degraded, increasing the concentration in a blood draw.”

The other priming agent they developed is a nanoparticle designed to block macrophages from taking up cell-free DNA. These cells have a well-known tendency to eat up synthetic nanoparticles.

“DNA is a biological nanoparticle, and it made sense that immune cells in the liver were probably taking this up just like they do synthetic nanoparticles. And if that were the case, which it turned out to be, then we could use a safe dummy nanoparticle to distract those immune cells and leave the circulating DNA alone so that it could be at a higher concentration,” Bhatia says.

Earlier tumor detection

The researchers tested their priming agents in mice that received transplants of cancer cells that tend to form tumors in the lungs. Two weeks after the cells were transplanted, the researchers showed that these priming agents could boost the amount of circulating tumor DNA recovered in a blood sample by up to 60-fold.

Once the blood sample is taken, it can be run through the same kinds of sequencing tests now used on liquid biopsy samples. These tests can pick out tumor DNA, including specific sequences used to determine the type of tumor and potentially what kinds of treatments would work best.

Early detection of cancer is another promising application for these priming agents. The researchers found that when mice were given the nanoparticle priming agent before blood was drawn, it allowed them to detect circulating tumor DNA in blood of 75 percent of the mice with low cancer burden, while none were detectable without this boost.

“One of the greatest hurdles for cancer liquid biopsy testing has been the scarcity of circulating tumor DNA in a blood sample,” Adalsteinsson says. “It’s thus been encouraging to see the magnitude of the effect we’ve been able to achieve so far and to envision what impact this could have for patients.”

After either of the priming agents are injected, it takes an hour or two for the DNA levels to increase in the bloodstream, and then they return to normal within about 24 hours.

“The ability to get peak activity of these agents within a couple of hours, followed by their rapid clearance, means that someone could go into a doctor’s office, receive an agent like this, and then give their blood for the test itself, all within one visit,” Love says. “This feature bodes well for the potential to translate this concept into clinical use.”

The researchers have launched a company called Amplifyer Bio that plans to further develop the technology, in hopes of advancing to clinical trials.

“A tube of blood is a much more accessible diagnostic than colonoscopy screening or even mammography,” Bhatia says. “Ultimately, if these tools really are predictive, then we should be able to get many more patients into the system who could benefit from cancer interception or better therapy.”

The research was funded by the Koch Institute Support (core) Grant from the National Cancer Institute, the Marble Center for Cancer Nanomedicine, the Gerstner Family Foundation, the Ludwig Center at MIT, the Koch Institute Frontier Research Program via the Casey and Family Foundation, and the Bridge Project, a partnership between the Koch Institute and the Dana-Farber/Harvard Cancer Center.

© Image: MIT News; iStock

An MIT research team led by Professor Darrell Irvine has developed a novel kind of vaccine adjuvant: a nanoparticle that can help to stimulate the immune system to generate a stronger response to a vaccine. These nanoparticles contain saponin, a compound derived from the bark of the Chilean soapbark tree, along with a molecule called MPLA, each of which helps to activate the immune system.

The adjuvant has been incorporated into an experimental HIV vaccine that has shown promising results in animal studies, and this month, the first human volunteers will receive the vaccine as part of a phase 1 clinical trial run by the Consortium for HIV/AIDS Vaccine Development at the Scripps Research Institute. MIT News spoke with Irvine about why this project required an interdisciplinary approach, and what may lie ahead.

Q: What are the special features of the new nanoparticle adjuvant that help it create a more powerful immune response to vaccination? 

A: Most vaccines, such as the Covid-19 vaccines, are thought to protect us through B cells making protective antibodies. Development of an HIV vaccine has been made challenging by the fact that the B cells that are capable of evolving to produce protective antibodies — called broadly neutralizing antibodies — are very rare in the average person. Vaccine adjuvants are important in this scenario to ensure that when we immunize with an HIV antigen, these rare B cells become activated and get a chance to participate in the immune response.

We particularly discovered that this new adjuvant, which we call SMNP (short for saponin/MPLA nanoparticles), is particularly good at helping more B cells enter germinal centers, the specialized location in lymph nodes where high affinity antibodies are produced. In animal models, SMNP also has shown unique mechanisms of action: Administering antigens with SMNP leads to better antigen delivery to lymph nodes (through increases in lymph flow) and better capture of the antigen by B cells in lymph nodes.

Q: How did your lab, which generally focuses on bioengineering and materials science, end up working on HIV vaccines? What obstacles did you have to overcome in the development of this adjuvant?

A: About 15 years ago, Bruce Walker approached me about getting involved in the HIV vaccine effort, and recruited me to join the Ragon Institute of MGH, MIT, and Harvard as a member of the steering committee. Through the Ragon Institute, I met colleagues in the Scripps Consortium for HIV/AIDS Vaccine Development (CHAVD), and we realized there was a tremendous opportunity to directly contribute to the HIV vaccine challenge, working in partnership with experts in immunogen design, structural biology, and HIV pathogenesis.

As we carried out study after study of SMNP in preclinical animal models, we realized the adjuvant had really amazing effects for promoting anti-HIV antibody responses, and the CHAVD decided this was worth moving forward to testing in humans. A major challenge was transferring the technology out of the lab to synthesize large amounts of the adjuvant under GMP (good manufacturing process) conditions for a clinical trial. The initial contract manufacturing organization (CMO) hired by the consortium to produce SMNP simply couldn’t get a process to work for scalable manufacturing.

Luckily for us, a chemical engineering graduate student, Ivan Pires, whom I co-advise with Paula Hammond, head of MIT’s Department of Chemical Engineering, had developed expertise in one particular processing technique known as tangential flow filtration during his undergraduate training. Leveraging classic chemical engineering skills in thermodynamics and process design, Ivan stepped in and solved the process issues the CMO was facing, allowing the manufacturing to move forward. This to me is what makes MIT great — the ability of our students and postdocs to step up and solve big problems and make big contributions when the need arises.

Q: What other diseases could this approach be useful for? Are there any plans to test it with other types of vaccines?

A: In principle, SMNP may be helpful for any infectious disease vaccine where strong antibody responses are needed. We are currently sharing the adjuvant with about 30 different labs around the world, who are testing it in vaccines against many other pathogens including Epstein-Barr virus, malaria, and influenza. We are hopeful that if SMNP is safe and effective in humans, this will be an adjuvant that can be broadly used in infectious disease trials.

© Photo: Steve Boxall

When Paula Hammond first arrived on MIT’s campus as a first-year student in the early 1980s, she wasn’t sure if she belonged. In fact, as she told an MIT audience yesterday, she felt like “an imposter.”

However, that feeling didn’t last long, as Hammond began to find support among her fellow students and MIT’s faculty. “Community was really important for me, to feel that I belonged, to feel that I had a place here, and I found people who were willing to embrace me and support me,” she said.

Hammond, a world-renowned chemical engineer who has spent most of her academic career at MIT, made her remarks during the 2023-24 James R. Killian Jr. Faculty Achievement Award lecture.

Established in 1971 to honor MIT’s 10th president, James Killian, the Killian Award recognizes extraordinary professional achievements by an MIT faculty member. Hammond was chosen for this year’s award “not only for her tremendous professional achievements and contributions, but also for her genuine warmth and humanity, her thoughtfulness and effective leadership, and her empathy and ethics,” according to the award citation.

“Professor Hammond is a pioneer in nanotechnology research. With a program that extends from basic science to translational research in medicine and energy, she has introduced new approaches for the design and development of complex drug delivery systems for cancer treatment and noninvasive imaging,” said Mary Fuller, chair of MIT’s faculty and a professor of literature, who presented the award. “As her colleagues, we are delighted to celebrate her career today.”

In January, Hammond began serving as MIT’s vice provost for faculty. Before that, she chaired the Department of Chemical Engineering for eight years, and she was named an Institute Professor in 2021.

A versatile technique

Hammond, who grew up in Detroit, credits her parents with instilling a love of science. Her father was one of very few Black PhDs in biochemistry at the time, while her mother earned a master’s degree in nursing from Howard University and founded the nursing school at Wayne County Community College. “That provided a huge amount of opportunity for women in the area of Detroit, including women of color,” Hammond noted.

After earning her bachelor’s degree from MIT in 1984, Hammond worked as an engineer before returning to the Institute as a graduate student, earning her PhD in 1993. After a two-year postdoc at Harvard University, she returned to join the MIT faculty in 1995.

At the heart of Hammond’s research is a technique she developed to create thin films that can essentially “shrink-wrap” nanoparticles. By tuning the chemical composition of these films, the particles can be customized to deliver drugs or nucleic acids and to target specific cells in the body, including cancer cells.

To make these films, Hammond begins by layering positively charged polymers onto a negatively charged surface. Then, more layers can be added, alternating positively and negatively charged polymers. Each of these layers may contain drugs or other useful molecules, such as DNA or RNA. Some of these films contain hundreds of layers, others just one, making them useful for a wide range of applications.

“What’s nice about the layer-by-layer process is I can choose a group of degradable polymers that are nicely biocompatible, and I can alternate them with our drug materials. This means that I can build up thin film layers that contain different drugs at different points within the film,” Hammond said. “Then, when the film degrades, it can release those drugs in reverse order. This is enabling us to create complex, multidrug films, using a simple water-based technique.”

Hammond described how these layer-by-layer films can be used to promote bone growth, in an application that could help people born with congenital bone defects or people who experience traumatic injuries.

For that use, her lab has created films with layers of two proteins. One of these, BMP-2, is a protein that interacts with adult stem cells and induces them to differentiate into bone cells, generating new bone. The second is a growth factor called VEGF, which stimulates the growth of new blood vessels that help bone to regenerate. These layers are applied to a very thin tissue scaffold that can be implanted at the injury site.

Hammond and her students designed the coating so that once implanted, it would release VEGF early, over a week or so, and continue releasing BMP-2 for up to 40 days. In a study of mice, they found that this tissue scaffold stimulated the growth of new bone that was nearly indistinguishable from natural bone.

Targeting cancer

As a member of MIT’s Koch Institute for Integrative Cancer Research, Hammond has also developed layer-by-layer coatings that can improve the performance of nanoparticles used for cancer drug delivery, such as liposomes or nanoparticles made from a polymer called PLGA.

“We have a broad range of drug carriers that we can wrap this way. I think of them like a gobstopper, where there are all those different layers of candy and they dissolve one at a time,” Hammond said.

Using this approach, Hammond has created particles that can deliver a one-two punch to cancer cells. First, the particles release a dose of a nucleic acid such as short interfering RNA (siRNA), which can turn off a cancerous gene, or microRNA, which can activate tumor suppressor genes. Then, the particles release a chemotherapy drug such as cisplatin, to which the cells are now more vulnerable.

The particles also include a negatively charged outer “stealth layer” that protects them from being broken down in the bloodstream before they can reach their targets. This outer layer can also be modified to help the particles get taken up by cancer cells, by incorporating molecules that bind to proteins that are abundant on tumor cells.

In more recent work, Hammond has begun developing nanoparticles that can target ovarian cancer and help prevent recurrence of the disease after chemotherapy. In about 70 percent of ovarian cancer patients, the first round of treatment is highly effective, but tumors recur in about 85 percent of those cases, and these new tumors are usually highly drug resistant.

By altering the type of coating applied to drug-delivering nanoparticles, Hammond has found that the particles can be designed to either get inside tumor cells or stick to their surfaces. Using particles that stick to the cells, she has designed a treatment that could help to jumpstart a patient’s immune response to any recurrent tumor cells.

“With ovarian cancer, very few immune cells exist in that space, and because they don’t have a lot of immune cells present, it’s very difficult to rev up an immune response,” she said. “However, if we can deliver a molecule to neighboring cells, those few that are present, and get them revved up, then we might be able to do something.”

To that end, she designed nanoparticles that deliver IL-12, a cytokine that stimulates nearby T cells to spring into action and begin attacking tumor cells. In a study of mice, she found that this treatment induced a long-term memory T-cell response that prevented recurrence of ovarian cancer.

Hammond closed her lecture by describing the impact that the Institute has had on her throughout her career.

“It’s been a transformative experience,” she said. “I really think of this place as special because it brings people together and enables us to do things together that we couldn’t do alone. And it is that support we get from our friends, our colleagues, and our students that really makes things possible.”

© Photo: Jake Belcher

Many vaccines, including vaccines for hepatitis B and whooping cough, consist of fragments of viral or bacterial proteins. These vaccines often include other molecules called adjuvants, which help to boost the immune system’s response to the protein.

Most of these adjuvants consist of aluminum salts or other molecules that provoke a nonspecific immune response. A team of MIT researchers has now shown that a type of nanoparticle called a metal organic framework (MOF) can also provoke a strong immune response, by activating the innate immune system — the body’s first line of defense against any pathogen — through cell proteins called toll-like receptors.

In a study of mice, the researchers showed that this MOF could successfully encapsulate and deliver part of the SARS-CoV-2 spike protein, while also acting as an adjuvant once the MOF is broken down inside cells.

While more work would be needed to adapt these particles for use as vaccines, the study demonstrates that this type of structure can be useful for generating a strong immune response, the researchers say.

“Understanding how the drug delivery vehicle can enhance an adjuvant immune response is something that could be very helpful in designing new vaccines,” says Ana Jaklenec, a principal investigator at MIT’s Koch Institute for Integrative Cancer Research and one of the senior authors of the new study.

Robert Langer, an MIT Institute Professor and member of the Koch Institute, and Dan Barouch, director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center and a professor at Harvard Medical School, are also senior authors of the paper, which appears today in Science Advances. The paper’s lead author is former MIT postdoc and Ibn Khaldun Fellow Shahad Alsaiari.

Immune activation

In this study, the researchers focused on a MOF called ZIF-8, which consists of a lattice of tetrahedral units made up of a zinc ion attached to four molecules of imidazole, an organic compound. Previous work has shown that ZIF-8 can significantly boost immune responses, but it wasn’t known exactly how this particle activates the immune system.

To try to figure that out, the MIT team created an experimental vaccine consisting of the SARS-CoV-2 receptor-binding protein (RBD) embedded within ZIF-8 particles. These particles are between 100 and 200 nanometers in diameter, a size that allows them to get into the body’s lymph nodes directly or through immune cells such as macrophages.

Once the particles enter the cells, the MOFs are broken down, releasing the viral proteins. The researchers found that the imidazole components then activate toll-like receptors (TLRs), which help to stimulate the innate immune response.

“This process is analogous to establishing a covert operative team at the molecular level to transport essential elements of the Covid-19 virus to the body’s immune system, where they can activate specific immune responses to boost vaccine efficacy,” Alsaiari says.

RNA sequencing of cells from the lymph nodes showed that mice vaccinated with ZIF-8 particles carrying the viral protein strongly activated a TLR pathway known as TLR-7, which led to greater production of cytokines and other molecules involved in inflammation.

Mice vaccinated with these particles generated a much stronger response to the viral protein than mice that received the protein on its own.

“Not only are we delivering the protein in a more controlled way through a nanoparticle, but the compositional structure of this particle is also acting as an adjuvant,” Jaklenec says. “We were able to achieve very specific responses to the Covid protein, and with a dose-sparing effect compared to using the protein by itself to vaccinate.”

Vaccine access

While this study and others have demonstrated ZIF-8’s immunogenic ability, more work needs to be done to evaluate the particles’ safety and potential to be scaled up for large-scale manufacturing. If ZIF-8 is not developed as a vaccine carrier, the findings from the study should help to guide researchers in developing similar nanoparticles that could be used to deliver subunit vaccines, Jaklenec says.

“Most subunit vaccines usually have two separate components: an antigen and an adjuvant,” Jaklenec says. “Designing new vaccines that utilize nanoparticles with specific chemical moieties which not only aid in antigen delivery but can also activate particular immune pathways have the potential to enhance vaccine potency.”

One advantage to developing a subunit vaccine for Covid-19 is that such vaccines are usually easier and cheaper to manufacture than mRNA vaccines, which could make it easier to distribute them around the world, the researchers say.

“Subunit vaccines have been around for a long time, and they tend to be cheaper to produce, so that opens up more access to vaccines, especially in times of pandemic,” Jaklenec says.

The research was funded by Ibn Khaldun Fellowships for Saudi Arabian Women and in part by the Koch Institute Support (core) Grant from the U.S. National Cancer Institute.

© Image: Courtesy of the researchers

A team of MIT researchers will lead a $65.67 million effort, awarded by the U.S. Advanced Research Projects Agency for Health (ARPA-H), to develop ingestible devices that may one day be used to treat diabetes, obesity, and other conditions through oral delivery of mRNA. Such devices could potentially be deployed for needle-free delivery of mRNA vaccines as well.

The five-year project also aims to develop electroceuticals, a new form of ingestible therapies based on electrical stimulation of the body’s own hormones and neural signaling. If successful, this approach could lead to new treatments for a variety of metabolic disorders.

“We know that the oral route is generally the preferred route of administration for both patients and health care providers,” says Giovanni Traverso, an associate professor of mechanical engineering at MIT and a gastroenterologist at Brigham and Women’s Hospital. “Our primary focus is on disorders of metabolism because they affect a lot of people, but the platforms we’re developing could be applied very broadly.”

Traverso is the principal investigator for the project, which also includes Robert Langer, MIT Institute Professor, and Anantha Chandrakasan, dean of the MIT School of Engineering and the Vannevar Bush Professor of Electrical Engineering and Computer Science. As part of the project, the MIT team will collaborate with investigators from Brigham and Women’s Hospital, New York University, and the University of Colorado School of Medicine.

Over the past several years, Traverso’s and Langer’s labs have designed many types of ingestible devices that can deliver drugs to the GI tract. This approach could be especially useful for protein drugs and nucleic acids, which typically can’t be given orally because they break down in the acidic environment of the digestive tract.

Messenger RNA has already proven useful as a vaccine, directing cells to produce fragments of viral proteins that trigger an immune response. Delivering mRNA to cells also holds potential to stimulate production of therapeutic molecules to treat a variety of diseases. In this project, the researchers plan to focus on metabolic diseases such as diabetes.

“What mRNA can do is enable the potential for dosing therapies that are very difficult to dose today, or provide longer-term coverage by essentially creating an internal factory that produces a therapy for a prolonged period,” Traverso says.

In the mRNA portion of the project, the research team intends to identify lipid and polymer nanoparticle formulations that can most effectively deliver mRNA to cells, using machine learning to help identify the best candidates. They will also develop and test ingestible devices to carry the mRNA-nanoparticle payload, with the goal of running a clinical trial in the final year of the five-year project.

The work will build on research that Traverso’s lab has already begun. In 2022, Traverso and his colleagues reported that they could deliver mRNA in capsules that inject mRNA-nanoparticle complexes into the lining of the stomach.

The other branch of the project will focus on ingestible devices that can deliver a small electrical current to the lining of the stomach. In a study published last year, Traverso’s lab demonstrated this approach for the first time, using a capsule coated with electrodes that apply an electrical current to cells of the stomach. In animal studies, they found that this stimulation boosted production of ghrelin, a hormone that stimulates appetite.

Traverso envisions that this type of treatment could potentially replace or complement some of the existing drugs used to prevent nausea and stimulate appetite in people with anorexia or cachexia (loss of body mass that can occur in patients with cancer or other chronic diseases). The researchers also hope to develop ways to stimulate production of GLP-1, a hormone that is used to help manage diabetes and promote weight loss.

“What this approach starts to do is potentially maximize our ability to treat disease without administering a new drug, but instead by simply modulating the body’s own systems through electrical stimulation,” Traverso says.

At MIT, Langer will help to develop nanoparticles for mRNA delivery, and Chandrakasan will work on ways to reduce energy consumption and miniaturize the electronic functions of the capsules, including secure communication, stimulation, and power generation.

The Brigham and Women’s Hospital’s portion of the project will be co-led by Traverso, Ameya Kirtane, Jason Li, and Peter Chai, who will amplify efforts on the formulation and stabilization of the mRNA nanoparticles, engineering of the ingestible devices, and running of clinical trials. At NYU, the effort will be led by assistant professor of bioengineering Khalil Ramadi SM ’16, PhD ’19, focusing on biological characterization of the effects of electrical stimulation. Researchers at the University of Colorado, led by Matthew Wynia and Eric G. Campbell of the CU Center for Bioethics and Humanities, will focus on exploring the ethical dimensions and public perceptions of these types of biomedical interventions.

“We felt like we had an opportunity here not only to do fundamental engineering science and early-stage clinical trials, but also to start to understand the data behind some of the ethical implications and public perceptions of these technologies through this broad collaboration,” Traverso says.

The project described here is supported by ARPA-H under award number D24AC00040-00. The content of this announcement does not necessarily represent the official views of the Advanced Research Projects Agency for Health.

© Image: Courtesy of MechE

Using a virus-like delivery particle made from DNA, researchers from MIT and the Ragon Institute of MGH, MIT, and Harvard have created a vaccine that can induce a strong antibody response against SARS-CoV-2.

The vaccine, which has been tested in mice, consists of a DNA scaffold that carries many copies of a viral antigen. This type of vaccine, known as a particulate vaccine, mimics the structure of a virus. Most previous work on particulate vaccines has relied on protein scaffolds, but the proteins used in those vaccines tend to generate an unnecessary immune response that can distract the immune system from the target.

In the mouse study, the researchers found that the DNA scaffold does not induce an immune response, allowing the immune system to focus its antibody response on the target antigen.

“DNA, we found in this work, does not elicit antibodies that may distract away from the protein of interest,” says Mark Bathe, an MIT professor of biological engineering. “What you can imagine is that your B cells and immune system are being fully trained by that target antigen, and that’s what you want — for your immune system to be laser-focused on the antigen of interest.”

This approach, which strongly stimulates B cells (the cells that produce antibodies), could make it easier to develop vaccines against viruses that have been difficult to target, including HIV and influenza, as well as SARS-CoV-2, the researchers say. Unlike T cells, which are stimulated by other types of vaccines, these B cells can persist for decades, offering long-term protection.

“We’re interested in exploring whether we can teach the immune system to deliver higher levels of immunity against pathogens that resist conventional vaccine approaches, like flu, HIV, and SARS-CoV-2,” says Daniel Lingwood, an associate professor at Harvard Medical School and a principal investigator at the Ragon Institute. “This idea of decoupling the response against the target antigen from the platform itself is a potentially powerful immunological trick that one can now bring to bear to help those immunological targeting decisions move in a direction that is more focused.”

Bathe, Lingwood, and Aaron Schmidt, an associate professor at Harvard Medical School and principal investigator at the Ragon Institute, are the senior authors of the paper, which appears today in Nature Communications. The paper’s lead authors are Eike-Christian Wamhoff, a former MIT postdoc; Larance Ronsard, a Ragon Institute postdoc; Jared Feldman, a former Harvard University graduate student; Grant Knappe, an MIT graduate student; and Blake Hauser, a former Harvard graduate student. 

Mimicking viruses

Particulate vaccines usually consist of a protein nanoparticle, similar in structure to a virus, that can carry many copies of a viral antigen. This high density of antigens can lead to a stronger immune response than traditional vaccines because the body sees it as similar to an actual virus. Particulate vaccines have been developed for a handful of pathogens, including hepatitis B and human papillomavirus, and a particulate vaccine for SARS-CoV-2 has been approved for use in South Korea.

These vaccines are especially good at activating B cells, which produce antibodies specific to the vaccine antigen.

“Particulate vaccines are of great interest for many in immunology because they give you robust humoral immunity, which is antibody-based immunity, which is differentiated from the T-cell-based immunity that the mRNA vaccines seem to elicit more strongly,” Bathe says.

A potential drawback to this kind of vaccine, however, is that the proteins used for the scaffold often stimulate the body to produce antibodies targeting the scaffold. This can distract the immune system and prevent it from launching as robust a response as one would like, Bathe says.

“To neutralize the SARS-CoV-2 virus, you want to have a vaccine that generates antibodies toward the receptor binding domain portion of the virus’ spike protein,” he says. “When you display that on a protein-based particle, what happens is your immune system recognizes not only that receptor binding domain protein, but all the other proteins that are irrelevant to the immune response you’re trying to elicit.”

Another potential drawback is that if the same person receives more than one vaccine carried by the same protein scaffold, for example, SARS-CoV-2 and then influenza, their immune system would likely respond right away to the protein scaffold, having already been primed to react to it. This could weaken the immune response to the antigen carried by the second vaccine.

“If you want to apply that protein-based particle to immunize against a different virus like influenza, then your immune system can be addicted to the underlying protein scaffold that it’s already seen and developed an immune response toward,” Bathe says. “That can hypothetically diminish the quality of your antibody response for the actual antigen of interest.”

As an alternative, Bathe’s lab has been developing scaffolds made using DNA origami, a method that offers precise control over the structure of synthetic DNA and allows researchers to attach a variety of molecules, such as viral antigens, at specific locations.

In a 2020 study, Bathe and Darrell Irvine, an MIT professor of biological engineering and of materials science and engineering, showed that a DNA scaffold carrying 30 copies of an HIV antigen could generate a strong antibody response in B cells grown in the lab. This type of structure is optimal for activating B cells because it closely mimics the structure of nano-sized viruses, which display many copies of viral proteins in their surfaces.

“This approach builds off of a fundamental principle in B-cell antigen recognition, which is that if you have an arrayed display of the antigen, that promotes B-cell responses and gives better quantity and quality of antibody output,” Lingwood says.

“Immunologically silent”

In the new study, the researchers swapped in an antigen consisting of the receptor binding protein of the spike protein from the original strain of SARS-CoV-2. When they gave the vaccine to mice, they found that the mice generated high levels of antibodies to the spike protein but did not generate any to the DNA scaffold.

In contrast, a vaccine based on a scaffold protein called ferritin, coated with SARS-CoV-2 antigens, generated many antibodies against ferritin as well as SARS-CoV-2.

“The DNA nanoparticle itself is immunogenically silent,” Lingwood says. “If you use a protein-based platform, you get equally high titer antibody responses to the platform and to the antigen of interest, and that can complicate repeated usage of that platform because you’ll develop high affinity immune memory against it.”

Reducing these off-target effects could also help scientists reach the goal of developing a vaccine that would induce broadly neutralizing antibodies to any variant of SARS-CoV-2, or even to all sarbecoviruses, the subgenus of virus that includes SARS-CoV-2 as well as the viruses that cause SARS and MERS.

To that end, the researchers are now exploring whether a DNA scaffold with many different viral antigens attached could induce broadly neutralizing antibodies against SARS-CoV-2 and related viruses. 

The research was primarily funded by the National Institutes of Health, the National Science Foundation, and the Fast Grants program.

© Credit: The Bathe Lab

Tumors constantly shed DNA from dying cells, which briefly circulates in the patient’s bloodstream before it is quickly broken down. Many companies have created blood tests that can pick out this tumor DNA, potentially helping doctors diagnose or monitor cancer or choose a treatment.

The amount of tumor DNA circulating at any given time, however, is extremely small, so it has been challenging to develop tests sensitive enough to pick up that tiny signal. A team of researchers from MIT and the Broad Institute of MIT and Harvard has now come up with a way to significantly boost that signal, by temporarily slowing the clearance of tumor DNA circulating in the bloodstream.

The researchers developed two different types of injectable molecules that they call “priming agents,” which can transiently interfere with the body’s ability to remove circulating tumor DNA from the bloodstream. In a study of mice, they showed that these agents could boost DNA levels enough that the percentage of detectable early-stage lung metastases leapt from less than 10 percent to above 75 percent.

This approach could enable not only earlier diagnosis of cancer, but also more sensitive detection of tumor mutations that could be used to guide treatment. It could also help improve detection of cancer recurrence.

“You can give one of these agents an hour before the blood draw, and it makes things visible that previously wouldn’t have been. The implication is that we should be able to give everybody who’s doing liquid biopsies, for any purpose, more molecules to work with,” says Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and of Electrical Engineering and Computer Science at MIT, and a member of MIT’s Koch Institute for Integrative Cancer Research and the Institute for Medical Engineering and Science.

Bhatia is one of the senior authors of the new study, along with J. Christopher Love, the Raymond A. and Helen E. St. Laurent Professor of Chemical Engineering at MIT and a member of the Koch Institute and the Ragon Institute of MGH, MIT, and Harvard and Viktor Adalsteinsson, director of the Gerstner Center for Cancer Diagnostics at the Broad Institute.

Carmen Martin-Alonso PhD ’23, MIT and Broad Institute postdoc Shervin Tabrizi, and Broad Institute scientist Kan Xiong are the lead authors of the paper, which appears today in Science.

Better biopsies

Liquid biopsies, which enable detection of small quantities of DNA in blood samples, are now used in many cancer patients to identify mutations that could help guide treatment. With greater sensitivity, however, these tests could become useful for far more patients. Most efforts to improve the sensitivity of liquid biopsies have focused on developing new sequencing technologies to use after the blood is drawn.

While brainstorming ways to make liquid biopsies more informative, Bhatia, Love, Adalsteinsson, and their trainees came up with the idea of trying to increase the amount of DNA in a patient’s bloodstream before the sample is taken.

“A tumor is always creating new cell-free DNA, and that’s the signal that we’re attempting to detect in the blood draw. Existing liquid biopsy technologies, however, are limited by the amount of material you collect in the tube of blood,” Love says. “Where this work intercedes is thinking about how to inject something beforehand that would help boost or enhance the amount of signal that is available to collect in the same small sample.”

The body uses two primary strategies to remove circulating DNA from the bloodstream. Enzymes called DNases circulate in the blood and break down DNA that they encounter, while immune cells known as macrophages take up cell-free DNA as blood is filtered through the liver.

The researchers decided to target each of these processes separately. To prevent DNases from breaking down DNA, they designed a monoclonal antibody that binds to circulating DNA and protects it from the enzymes.

“Antibodies are well-established biopharmaceutical modalities, and they’re safe in a number of different disease contexts, including cancer and autoimmune treatments,” Love says. “The idea was, could we use this kind of antibody to help shield the DNA temporarily from degradation by the nucleases that are in circulation? And by doing so, we shift the balance to where the tumor is generating DNA slightly faster than is being degraded, increasing the concentration in a blood draw.”

The other priming agent they developed is a nanoparticle designed to block macrophages from taking up cell-free DNA. These cells have a well-known tendency to eat up synthetic nanoparticles.

“DNA is a biological nanoparticle, and it made sense that immune cells in the liver were probably taking this up just like they do synthetic nanoparticles. And if that were the case, which it turned out to be, then we could use a safe dummy nanoparticle to distract those immune cells and leave the circulating DNA alone so that it could be at a higher concentration,” Bhatia says.

Earlier tumor detection

The researchers tested their priming agents in mice that received transplants of cancer cells that tend to form tumors in the lungs. Two weeks after the cells were transplanted, the researchers showed that these priming agents could boost the amount of circulating tumor DNA recovered in a blood sample by up to 60-fold.

Once the blood sample is taken, it can be run through the same kinds of sequencing tests now used on liquid biopsy samples. These tests can pick out tumor DNA, including specific sequences used to determine the type of tumor and potentially what kinds of treatments would work best.

Early detection of cancer is another promising application for these priming agents. The researchers found that when mice were given the nanoparticle priming agent before blood was drawn, it allowed them to detect circulating tumor DNA in blood of 75 percent of the mice with low cancer burden, while none were detectable without this boost.

“One of the greatest hurdles for cancer liquid biopsy testing has been the scarcity of circulating tumor DNA in a blood sample,” Adalsteinsson says. “It’s thus been encouraging to see the magnitude of the effect we’ve been able to achieve so far and to envision what impact this could have for patients.”

After either of the priming agents are injected, it takes an hour or two for the DNA levels to increase in the bloodstream, and then they return to normal within about 24 hours.

“The ability to get peak activity of these agents within a couple of hours, followed by their rapid clearance, means that someone could go into a doctor’s office, receive an agent like this, and then give their blood for the test itself, all within one visit,” Love says. “This feature bodes well for the potential to translate this concept into clinical use.”

The researchers have launched a company called Amplifyer Bio that plans to further develop the technology, in hopes of advancing to clinical trials.

“A tube of blood is a much more accessible diagnostic than colonoscopy screening or even mammography,” Bhatia says. “Ultimately, if these tools really are predictive, then we should be able to get many more patients into the system who could benefit from cancer interception or better therapy.”

The research was funded by the Koch Institute Support (core) Grant from the National Cancer Institute, the Marble Center for Cancer Nanomedicine, the Gerstner Family Foundation, the Ludwig Center at MIT, the Koch Institute Frontier Research Program via the Casey and Family Foundation, and the Bridge Project, a partnership between the Koch Institute and the Dana-Farber/Harvard Cancer Center.

© Image: MIT News; iStock

An MIT research team led by Professor Darrell Irvine has developed a novel kind of vaccine adjuvant: a nanoparticle that can help to stimulate the immune system to generate a stronger response to a vaccine. These nanoparticles contain saponin, a compound derived from the bark of the Chilean soapbark tree, along with a molecule called MPLA, each of which helps to activate the immune system.

The adjuvant has been incorporated into an experimental HIV vaccine that has shown promising results in animal studies, and this month, the first human volunteers will receive the vaccine as part of a phase 1 clinical trial run by the Consortium for HIV/AIDS Vaccine Development at the Scripps Research Institute. MIT News spoke with Irvine about why this project required an interdisciplinary approach, and what may lie ahead.

Q: What are the special features of the new nanoparticle adjuvant that help it create a more powerful immune response to vaccination? 

A: Most vaccines, such as the Covid-19 vaccines, are thought to protect us through B cells making protective antibodies. Development of an HIV vaccine has been made challenging by the fact that the B cells that are capable of evolving to produce protective antibodies — called broadly neutralizing antibodies — are very rare in the average person. Vaccine adjuvants are important in this scenario to ensure that when we immunize with an HIV antigen, these rare B cells become activated and get a chance to participate in the immune response.

We particularly discovered that this new adjuvant, which we call SMNP (short for saponin/MPLA nanoparticles), is particularly good at helping more B cells enter germinal centers, the specialized location in lymph nodes where high affinity antibodies are produced. In animal models, SMNP also has shown unique mechanisms of action: Administering antigens with SMNP leads to better antigen delivery to lymph nodes (through increases in lymph flow) and better capture of the antigen by B cells in lymph nodes.

Q: How did your lab, which generally focuses on bioengineering and materials science, end up working on HIV vaccines? What obstacles did you have to overcome in the development of this adjuvant?

A: About 15 years ago, Bruce Walker approached me about getting involved in the HIV vaccine effort, and recruited me to join the Ragon Institute of MGH, MIT, and Harvard as a member of the steering committee. Through the Ragon Institute, I met colleagues in the Scripps Consortium for HIV/AIDS Vaccine Development (CHAVD), and we realized there was a tremendous opportunity to directly contribute to the HIV vaccine challenge, working in partnership with experts in immunogen design, structural biology, and HIV pathogenesis.

As we carried out study after study of SMNP in preclinical animal models, we realized the adjuvant had really amazing effects for promoting anti-HIV antibody responses, and the CHAVD decided this was worth moving forward to testing in humans. A major challenge was transferring the technology out of the lab to synthesize large amounts of the adjuvant under GMP (good manufacturing process) conditions for a clinical trial. The initial contract manufacturing organization (CMO) hired by the consortium to produce SMNP simply couldn’t get a process to work for scalable manufacturing.

Luckily for us, a chemical engineering graduate student, Ivan Pires, whom I co-advise with Paula Hammond, head of MIT’s Department of Chemical Engineering, had developed expertise in one particular processing technique known as tangential flow filtration during his undergraduate training. Leveraging classic chemical engineering skills in thermodynamics and process design, Ivan stepped in and solved the process issues the CMO was facing, allowing the manufacturing to move forward. This to me is what makes MIT great — the ability of our students and postdocs to step up and solve big problems and make big contributions when the need arises.

Q: What other diseases could this approach be useful for? Are there any plans to test it with other types of vaccines?

A: In principle, SMNP may be helpful for any infectious disease vaccine where strong antibody responses are needed. We are currently sharing the adjuvant with about 30 different labs around the world, who are testing it in vaccines against many other pathogens including Epstein-Barr virus, malaria, and influenza. We are hopeful that if SMNP is safe and effective in humans, this will be an adjuvant that can be broadly used in infectious disease trials.

© Photo: Steve Boxall

When Paula Hammond first arrived on MIT’s campus as a first-year student in the early 1980s, she wasn’t sure if she belonged. In fact, as she told an MIT audience yesterday, she felt like “an imposter.”

However, that feeling didn’t last long, as Hammond began to find support among her fellow students and MIT’s faculty. “Community was really important for me, to feel that I belonged, to feel that I had a place here, and I found people who were willing to embrace me and support me,” she said.

Hammond, a world-renowned chemical engineer who has spent most of her academic career at MIT, made her remarks during the 2023-24 James R. Killian Jr. Faculty Achievement Award lecture.

Established in 1971 to honor MIT’s 10th president, James Killian, the Killian Award recognizes extraordinary professional achievements by an MIT faculty member. Hammond was chosen for this year’s award “not only for her tremendous professional achievements and contributions, but also for her genuine warmth and humanity, her thoughtfulness and effective leadership, and her empathy and ethics,” according to the award citation.

“Professor Hammond is a pioneer in nanotechnology research. With a program that extends from basic science to translational research in medicine and energy, she has introduced new approaches for the design and development of complex drug delivery systems for cancer treatment and noninvasive imaging,” said Mary Fuller, chair of MIT’s faculty and a professor of literature, who presented the award. “As her colleagues, we are delighted to celebrate her career today.”

In January, Hammond began serving as MIT’s vice provost for faculty. Before that, she chaired the Department of Chemical Engineering for eight years, and she was named an Institute Professor in 2021.

A versatile technique

Hammond, who grew up in Detroit, credits her parents with instilling a love of science. Her father was one of very few Black PhDs in biochemistry at the time, while her mother earned a master’s degree in nursing from Howard University and founded the nursing school at Wayne County Community College. “That provided a huge amount of opportunity for women in the area of Detroit, including women of color,” Hammond noted.

After earning her bachelor’s degree from MIT in 1984, Hammond worked as an engineer before returning to the Institute as a graduate student, earning her PhD in 1993. After a two-year postdoc at Harvard University, she returned to join the MIT faculty in 1995.

At the heart of Hammond’s research is a technique she developed to create thin films that can essentially “shrink-wrap” nanoparticles. By tuning the chemical composition of these films, the particles can be customized to deliver drugs or nucleic acids and to target specific cells in the body, including cancer cells.

To make these films, Hammond begins by layering positively charged polymers onto a negatively charged surface. Then, more layers can be added, alternating positively and negatively charged polymers. Each of these layers may contain drugs or other useful molecules, such as DNA or RNA. Some of these films contain hundreds of layers, others just one, making them useful for a wide range of applications.

“What’s nice about the layer-by-layer process is I can choose a group of degradable polymers that are nicely biocompatible, and I can alternate them with our drug materials. This means that I can build up thin film layers that contain different drugs at different points within the film,” Hammond said. “Then, when the film degrades, it can release those drugs in reverse order. This is enabling us to create complex, multidrug films, using a simple water-based technique.”

Hammond described how these layer-by-layer films can be used to promote bone growth, in an application that could help people born with congenital bone defects or people who experience traumatic injuries.

For that use, her lab has created films with layers of two proteins. One of these, BMP-2, is a protein that interacts with adult stem cells and induces them to differentiate into bone cells, generating new bone. The second is a growth factor called VEGF, which stimulates the growth of new blood vessels that help bone to regenerate. These layers are applied to a very thin tissue scaffold that can be implanted at the injury site.

Hammond and her students designed the coating so that once implanted, it would release VEGF early, over a week or so, and continue releasing BMP-2 for up to 40 days. In a study of mice, they found that this tissue scaffold stimulated the growth of new bone that was nearly indistinguishable from natural bone.

Targeting cancer

As a member of MIT’s Koch Institute for Integrative Cancer Research, Hammond has also developed layer-by-layer coatings that can improve the performance of nanoparticles used for cancer drug delivery, such as liposomes or nanoparticles made from a polymer called PLGA.

“We have a broad range of drug carriers that we can wrap this way. I think of them like a gobstopper, where there are all those different layers of candy and they dissolve one at a time,” Hammond said.

Using this approach, Hammond has created particles that can deliver a one-two punch to cancer cells. First, the particles release a dose of a nucleic acid such as short interfering RNA (siRNA), which can turn off a cancerous gene, or microRNA, which can activate tumor suppressor genes. Then, the particles release a chemotherapy drug such as cisplatin, to which the cells are now more vulnerable.

The particles also include a negatively charged outer “stealth layer” that protects them from being broken down in the bloodstream before they can reach their targets. This outer layer can also be modified to help the particles get taken up by cancer cells, by incorporating molecules that bind to proteins that are abundant on tumor cells.

In more recent work, Hammond has begun developing nanoparticles that can target ovarian cancer and help prevent recurrence of the disease after chemotherapy. In about 70 percent of ovarian cancer patients, the first round of treatment is highly effective, but tumors recur in about 85 percent of those cases, and these new tumors are usually highly drug resistant.

By altering the type of coating applied to drug-delivering nanoparticles, Hammond has found that the particles can be designed to either get inside tumor cells or stick to their surfaces. Using particles that stick to the cells, she has designed a treatment that could help to jumpstart a patient’s immune response to any recurrent tumor cells.

“With ovarian cancer, very few immune cells exist in that space, and because they don’t have a lot of immune cells present, it’s very difficult to rev up an immune response,” she said. “However, if we can deliver a molecule to neighboring cells, those few that are present, and get them revved up, then we might be able to do something.”

To that end, she designed nanoparticles that deliver IL-12, a cytokine that stimulates nearby T cells to spring into action and begin attacking tumor cells. In a study of mice, she found that this treatment induced a long-term memory T-cell response that prevented recurrence of ovarian cancer.

Hammond closed her lecture by describing the impact that the Institute has had on her throughout her career.

“It’s been a transformative experience,” she said. “I really think of this place as special because it brings people together and enables us to do things together that we couldn’t do alone. And it is that support we get from our friends, our colleagues, and our students that really makes things possible.”

© Photo: Jake Belcher

Many vaccines, including vaccines for hepatitis B and whooping cough, consist of fragments of viral or bacterial proteins. These vaccines often include other molecules called adjuvants, which help to boost the immune system’s response to the protein.

Most of these adjuvants consist of aluminum salts or other molecules that provoke a nonspecific immune response. A team of MIT researchers has now shown that a type of nanoparticle called a metal organic framework (MOF) can also provoke a strong immune response, by activating the innate immune system — the body’s first line of defense against any pathogen — through cell proteins called toll-like receptors.

In a study of mice, the researchers showed that this MOF could successfully encapsulate and deliver part of the SARS-CoV-2 spike protein, while also acting as an adjuvant once the MOF is broken down inside cells.

While more work would be needed to adapt these particles for use as vaccines, the study demonstrates that this type of structure can be useful for generating a strong immune response, the researchers say.

“Understanding how the drug delivery vehicle can enhance an adjuvant immune response is something that could be very helpful in designing new vaccines,” says Ana Jaklenec, a principal investigator at MIT’s Koch Institute for Integrative Cancer Research and one of the senior authors of the new study.

Robert Langer, an MIT Institute Professor and member of the Koch Institute, and Dan Barouch, director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center and a professor at Harvard Medical School, are also senior authors of the paper, which appears today in Science Advances. The paper’s lead author is former MIT postdoc and Ibn Khaldun Fellow Shahad Alsaiari.

Immune activation

In this study, the researchers focused on a MOF called ZIF-8, which consists of a lattice of tetrahedral units made up of a zinc ion attached to four molecules of imidazole, an organic compound. Previous work has shown that ZIF-8 can significantly boost immune responses, but it wasn’t known exactly how this particle activates the immune system.

To try to figure that out, the MIT team created an experimental vaccine consisting of the SARS-CoV-2 receptor-binding protein (RBD) embedded within ZIF-8 particles. These particles are between 100 and 200 nanometers in diameter, a size that allows them to get into the body’s lymph nodes directly or through immune cells such as macrophages.

Once the particles enter the cells, the MOFs are broken down, releasing the viral proteins. The researchers found that the imidazole components then activate toll-like receptors (TLRs), which help to stimulate the innate immune response.

“This process is analogous to establishing a covert operative team at the molecular level to transport essential elements of the Covid-19 virus to the body’s immune system, where they can activate specific immune responses to boost vaccine efficacy,” Alsaiari says.

RNA sequencing of cells from the lymph nodes showed that mice vaccinated with ZIF-8 particles carrying the viral protein strongly activated a TLR pathway known as TLR-7, which led to greater production of cytokines and other molecules involved in inflammation.

Mice vaccinated with these particles generated a much stronger response to the viral protein than mice that received the protein on its own.

“Not only are we delivering the protein in a more controlled way through a nanoparticle, but the compositional structure of this particle is also acting as an adjuvant,” Jaklenec says. “We were able to achieve very specific responses to the Covid protein, and with a dose-sparing effect compared to using the protein by itself to vaccinate.”

Vaccine access

While this study and others have demonstrated ZIF-8’s immunogenic ability, more work needs to be done to evaluate the particles’ safety and potential to be scaled up for large-scale manufacturing. If ZIF-8 is not developed as a vaccine carrier, the findings from the study should help to guide researchers in developing similar nanoparticles that could be used to deliver subunit vaccines, Jaklenec says.

“Most subunit vaccines usually have two separate components: an antigen and an adjuvant,” Jaklenec says. “Designing new vaccines that utilize nanoparticles with specific chemical moieties which not only aid in antigen delivery but can also activate particular immune pathways have the potential to enhance vaccine potency.”

One advantage to developing a subunit vaccine for Covid-19 is that such vaccines are usually easier and cheaper to manufacture than mRNA vaccines, which could make it easier to distribute them around the world, the researchers say.

“Subunit vaccines have been around for a long time, and they tend to be cheaper to produce, so that opens up more access to vaccines, especially in times of pandemic,” Jaklenec says.

The research was funded by Ibn Khaldun Fellowships for Saudi Arabian Women and in part by the Koch Institute Support (core) Grant from the U.S. National Cancer Institute.

© Image: Courtesy of the researchers

A team of MIT researchers will lead a $65.67 million effort, awarded by the U.S. Advanced Research Projects Agency for Health (ARPA-H), to develop ingestible devices that may one day be used to treat diabetes, obesity, and other conditions through oral delivery of mRNA. Such devices could potentially be deployed for needle-free delivery of mRNA vaccines as well.

The five-year project also aims to develop electroceuticals, a new form of ingestible therapies based on electrical stimulation of the body’s own hormones and neural signaling. If successful, this approach could lead to new treatments for a variety of metabolic disorders.

“We know that the oral route is generally the preferred route of administration for both patients and health care providers,” says Giovanni Traverso, an associate professor of mechanical engineering at MIT and a gastroenterologist at Brigham and Women’s Hospital. “Our primary focus is on disorders of metabolism because they affect a lot of people, but the platforms we’re developing could be applied very broadly.”

Traverso is the principal investigator for the project, which also includes Robert Langer, MIT Institute Professor, and Anantha Chandrakasan, dean of the MIT School of Engineering and the Vannevar Bush Professor of Electrical Engineering and Computer Science. As part of the project, the MIT team will collaborate with investigators from Brigham and Women’s Hospital, New York University, and the University of Colorado School of Medicine.

Over the past several years, Traverso’s and Langer’s labs have designed many types of ingestible devices that can deliver drugs to the GI tract. This approach could be especially useful for protein drugs and nucleic acids, which typically can’t be given orally because they break down in the acidic environment of the digestive tract.

Messenger RNA has already proven useful as a vaccine, directing cells to produce fragments of viral proteins that trigger an immune response. Delivering mRNA to cells also holds potential to stimulate production of therapeutic molecules to treat a variety of diseases. In this project, the researchers plan to focus on metabolic diseases such as diabetes.

“What mRNA can do is enable the potential for dosing therapies that are very difficult to dose today, or provide longer-term coverage by essentially creating an internal factory that produces a therapy for a prolonged period,” Traverso says.

In the mRNA portion of the project, the research team intends to identify lipid and polymer nanoparticle formulations that can most effectively deliver mRNA to cells, using machine learning to help identify the best candidates. They will also develop and test ingestible devices to carry the mRNA-nanoparticle payload, with the goal of running a clinical trial in the final year of the five-year project.

The work will build on research that Traverso’s lab has already begun. In 2022, Traverso and his colleagues reported that they could deliver mRNA in capsules that inject mRNA-nanoparticle complexes into the lining of the stomach.

The other branch of the project will focus on ingestible devices that can deliver a small electrical current to the lining of the stomach. In a study published last year, Traverso’s lab demonstrated this approach for the first time, using a capsule coated with electrodes that apply an electrical current to cells of the stomach. In animal studies, they found that this stimulation boosted production of ghrelin, a hormone that stimulates appetite.

Traverso envisions that this type of treatment could potentially replace or complement some of the existing drugs used to prevent nausea and stimulate appetite in people with anorexia or cachexia (loss of body mass that can occur in patients with cancer or other chronic diseases). The researchers also hope to develop ways to stimulate production of GLP-1, a hormone that is used to help manage diabetes and promote weight loss.

“What this approach starts to do is potentially maximize our ability to treat disease without administering a new drug, but instead by simply modulating the body’s own systems through electrical stimulation,” Traverso says.

At MIT, Langer will help to develop nanoparticles for mRNA delivery, and Chandrakasan will work on ways to reduce energy consumption and miniaturize the electronic functions of the capsules, including secure communication, stimulation, and power generation.

The Brigham and Women’s Hospital’s portion of the project will be co-led by Traverso, Ameya Kirtane, Jason Li, and Peter Chai, who will amplify efforts on the formulation and stabilization of the mRNA nanoparticles, engineering of the ingestible devices, and running of clinical trials. At NYU, the effort will be led by assistant professor of bioengineering Khalil Ramadi SM ’16, PhD ’19, focusing on biological characterization of the effects of electrical stimulation. Researchers at the University of Colorado, led by Matthew Wynia and Eric G. Campbell of the CU Center for Bioethics and Humanities, will focus on exploring the ethical dimensions and public perceptions of these types of biomedical interventions.

“We felt like we had an opportunity here not only to do fundamental engineering science and early-stage clinical trials, but also to start to understand the data behind some of the ethical implications and public perceptions of these technologies through this broad collaboration,” Traverso says.

The project described here is supported by ARPA-H under award number D24AC00040-00. The content of this announcement does not necessarily represent the official views of the Advanced Research Projects Agency for Health.

© Image: Courtesy of MechE

Using a virus-like delivery particle made from DNA, researchers from MIT and the Ragon Institute of MGH, MIT, and Harvard have created a vaccine that can induce a strong antibody response against SARS-CoV-2.

The vaccine, which has been tested in mice, consists of a DNA scaffold that carries many copies of a viral antigen. This type of vaccine, known as a particulate vaccine, mimics the structure of a virus. Most previous work on particulate vaccines has relied on protein scaffolds, but the proteins used in those vaccines tend to generate an unnecessary immune response that can distract the immune system from the target.

In the mouse study, the researchers found that the DNA scaffold does not induce an immune response, allowing the immune system to focus its antibody response on the target antigen.

“DNA, we found in this work, does not elicit antibodies that may distract away from the protein of interest,” says Mark Bathe, an MIT professor of biological engineering. “What you can imagine is that your B cells and immune system are being fully trained by that target antigen, and that’s what you want — for your immune system to be laser-focused on the antigen of interest.”

This approach, which strongly stimulates B cells (the cells that produce antibodies), could make it easier to develop vaccines against viruses that have been difficult to target, including HIV and influenza, as well as SARS-CoV-2, the researchers say. Unlike T cells, which are stimulated by other types of vaccines, these B cells can persist for decades, offering long-term protection.

“We’re interested in exploring whether we can teach the immune system to deliver higher levels of immunity against pathogens that resist conventional vaccine approaches, like flu, HIV, and SARS-CoV-2,” says Daniel Lingwood, an associate professor at Harvard Medical School and a principal investigator at the Ragon Institute. “This idea of decoupling the response against the target antigen from the platform itself is a potentially powerful immunological trick that one can now bring to bear to help those immunological targeting decisions move in a direction that is more focused.”

Bathe, Lingwood, and Aaron Schmidt, an associate professor at Harvard Medical School and principal investigator at the Ragon Institute, are the senior authors of the paper, which appears today in Nature Communications. The paper’s lead authors are Eike-Christian Wamhoff, a former MIT postdoc; Larance Ronsard, a Ragon Institute postdoc; Jared Feldman, a former Harvard University graduate student; Grant Knappe, an MIT graduate student; and Blake Hauser, a former Harvard graduate student. 

Mimicking viruses

Particulate vaccines usually consist of a protein nanoparticle, similar in structure to a virus, that can carry many copies of a viral antigen. This high density of antigens can lead to a stronger immune response than traditional vaccines because the body sees it as similar to an actual virus. Particulate vaccines have been developed for a handful of pathogens, including hepatitis B and human papillomavirus, and a particulate vaccine for SARS-CoV-2 has been approved for use in South Korea.

These vaccines are especially good at activating B cells, which produce antibodies specific to the vaccine antigen.

“Particulate vaccines are of great interest for many in immunology because they give you robust humoral immunity, which is antibody-based immunity, which is differentiated from the T-cell-based immunity that the mRNA vaccines seem to elicit more strongly,” Bathe says.

A potential drawback to this kind of vaccine, however, is that the proteins used for the scaffold often stimulate the body to produce antibodies targeting the scaffold. This can distract the immune system and prevent it from launching as robust a response as one would like, Bathe says.

“To neutralize the SARS-CoV-2 virus, you want to have a vaccine that generates antibodies toward the receptor binding domain portion of the virus’ spike protein,” he says. “When you display that on a protein-based particle, what happens is your immune system recognizes not only that receptor binding domain protein, but all the other proteins that are irrelevant to the immune response you’re trying to elicit.”

Another potential drawback is that if the same person receives more than one vaccine carried by the same protein scaffold, for example, SARS-CoV-2 and then influenza, their immune system would likely respond right away to the protein scaffold, having already been primed to react to it. This could weaken the immune response to the antigen carried by the second vaccine.

“If you want to apply that protein-based particle to immunize against a different virus like influenza, then your immune system can be addicted to the underlying protein scaffold that it’s already seen and developed an immune response toward,” Bathe says. “That can hypothetically diminish the quality of your antibody response for the actual antigen of interest.”

As an alternative, Bathe’s lab has been developing scaffolds made using DNA origami, a method that offers precise control over the structure of synthetic DNA and allows researchers to attach a variety of molecules, such as viral antigens, at specific locations.

In a 2020 study, Bathe and Darrell Irvine, an MIT professor of biological engineering and of materials science and engineering, showed that a DNA scaffold carrying 30 copies of an HIV antigen could generate a strong antibody response in B cells grown in the lab. This type of structure is optimal for activating B cells because it closely mimics the structure of nano-sized viruses, which display many copies of viral proteins in their surfaces.

“This approach builds off of a fundamental principle in B-cell antigen recognition, which is that if you have an arrayed display of the antigen, that promotes B-cell responses and gives better quantity and quality of antibody output,” Lingwood says.

“Immunologically silent”

In the new study, the researchers swapped in an antigen consisting of the receptor binding protein of the spike protein from the original strain of SARS-CoV-2. When they gave the vaccine to mice, they found that the mice generated high levels of antibodies to the spike protein but did not generate any to the DNA scaffold.

In contrast, a vaccine based on a scaffold protein called ferritin, coated with SARS-CoV-2 antigens, generated many antibodies against ferritin as well as SARS-CoV-2.

“The DNA nanoparticle itself is immunogenically silent,” Lingwood says. “If you use a protein-based platform, you get equally high titer antibody responses to the platform and to the antigen of interest, and that can complicate repeated usage of that platform because you’ll develop high affinity immune memory against it.”

Reducing these off-target effects could also help scientists reach the goal of developing a vaccine that would induce broadly neutralizing antibodies to any variant of SARS-CoV-2, or even to all sarbecoviruses, the subgenus of virus that includes SARS-CoV-2 as well as the viruses that cause SARS and MERS.

To that end, the researchers are now exploring whether a DNA scaffold with many different viral antigens attached could induce broadly neutralizing antibodies against SARS-CoV-2 and related viruses. 

The research was primarily funded by the National Institutes of Health, the National Science Foundation, and the Fast Grants program.

© Credit: The Bathe Lab

Tumors constantly shed DNA from dying cells, which briefly circulates in the patient’s bloodstream before it is quickly broken down. Many companies have created blood tests that can pick out this tumor DNA, potentially helping doctors diagnose or monitor cancer or choose a treatment.

The amount of tumor DNA circulating at any given time, however, is extremely small, so it has been challenging to develop tests sensitive enough to pick up that tiny signal. A team of researchers from MIT and the Broad Institute of MIT and Harvard has now come up with a way to significantly boost that signal, by temporarily slowing the clearance of tumor DNA circulating in the bloodstream.

The researchers developed two different types of injectable molecules that they call “priming agents,” which can transiently interfere with the body’s ability to remove circulating tumor DNA from the bloodstream. In a study of mice, they showed that these agents could boost DNA levels enough that the percentage of detectable early-stage lung metastases leapt from less than 10 percent to above 75 percent.

This approach could enable not only earlier diagnosis of cancer, but also more sensitive detection of tumor mutations that could be used to guide treatment. It could also help improve detection of cancer recurrence.

“You can give one of these agents an hour before the blood draw, and it makes things visible that previously wouldn’t have been. The implication is that we should be able to give everybody who’s doing liquid biopsies, for any purpose, more molecules to work with,” says Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and of Electrical Engineering and Computer Science at MIT, and a member of MIT’s Koch Institute for Integrative Cancer Research and the Institute for Medical Engineering and Science.

Bhatia is one of the senior authors of the new study, along with J. Christopher Love, the Raymond A. and Helen E. St. Laurent Professor of Chemical Engineering at MIT and a member of the Koch Institute and the Ragon Institute of MGH, MIT, and Harvard and Viktor Adalsteinsson, director of the Gerstner Center for Cancer Diagnostics at the Broad Institute.

Carmen Martin-Alonso PhD ’23, MIT and Broad Institute postdoc Shervin Tabrizi, and Broad Institute scientist Kan Xiong are the lead authors of the paper, which appears today in Science.

Better biopsies

Liquid biopsies, which enable detection of small quantities of DNA in blood samples, are now used in many cancer patients to identify mutations that could help guide treatment. With greater sensitivity, however, these tests could become useful for far more patients. Most efforts to improve the sensitivity of liquid biopsies have focused on developing new sequencing technologies to use after the blood is drawn.

While brainstorming ways to make liquid biopsies more informative, Bhatia, Love, Adalsteinsson, and their trainees came up with the idea of trying to increase the amount of DNA in a patient’s bloodstream before the sample is taken.

“A tumor is always creating new cell-free DNA, and that’s the signal that we’re attempting to detect in the blood draw. Existing liquid biopsy technologies, however, are limited by the amount of material you collect in the tube of blood,” Love says. “Where this work intercedes is thinking about how to inject something beforehand that would help boost or enhance the amount of signal that is available to collect in the same small sample.”

The body uses two primary strategies to remove circulating DNA from the bloodstream. Enzymes called DNases circulate in the blood and break down DNA that they encounter, while immune cells known as macrophages take up cell-free DNA as blood is filtered through the liver.

The researchers decided to target each of these processes separately. To prevent DNases from breaking down DNA, they designed a monoclonal antibody that binds to circulating DNA and protects it from the enzymes.

“Antibodies are well-established biopharmaceutical modalities, and they’re safe in a number of different disease contexts, including cancer and autoimmune treatments,” Love says. “The idea was, could we use this kind of antibody to help shield the DNA temporarily from degradation by the nucleases that are in circulation? And by doing so, we shift the balance to where the tumor is generating DNA slightly faster than is being degraded, increasing the concentration in a blood draw.”

The other priming agent they developed is a nanoparticle designed to block macrophages from taking up cell-free DNA. These cells have a well-known tendency to eat up synthetic nanoparticles.

“DNA is a biological nanoparticle, and it made sense that immune cells in the liver were probably taking this up just like they do synthetic nanoparticles. And if that were the case, which it turned out to be, then we could use a safe dummy nanoparticle to distract those immune cells and leave the circulating DNA alone so that it could be at a higher concentration,” Bhatia says.

Earlier tumor detection

The researchers tested their priming agents in mice that received transplants of cancer cells that tend to form tumors in the lungs. Two weeks after the cells were transplanted, the researchers showed that these priming agents could boost the amount of circulating tumor DNA recovered in a blood sample by up to 60-fold.

Once the blood sample is taken, it can be run through the same kinds of sequencing tests now used on liquid biopsy samples. These tests can pick out tumor DNA, including specific sequences used to determine the type of tumor and potentially what kinds of treatments would work best.

Early detection of cancer is another promising application for these priming agents. The researchers found that when mice were given the nanoparticle priming agent before blood was drawn, it allowed them to detect circulating tumor DNA in blood of 75 percent of the mice with low cancer burden, while none were detectable without this boost.

“One of the greatest hurdles for cancer liquid biopsy testing has been the scarcity of circulating tumor DNA in a blood sample,” Adalsteinsson says. “It’s thus been encouraging to see the magnitude of the effect we’ve been able to achieve so far and to envision what impact this could have for patients.”

After either of the priming agents are injected, it takes an hour or two for the DNA levels to increase in the bloodstream, and then they return to normal within about 24 hours.

“The ability to get peak activity of these agents within a couple of hours, followed by their rapid clearance, means that someone could go into a doctor’s office, receive an agent like this, and then give their blood for the test itself, all within one visit,” Love says. “This feature bodes well for the potential to translate this concept into clinical use.”

The researchers have launched a company called Amplifyer Bio that plans to further develop the technology, in hopes of advancing to clinical trials.

“A tube of blood is a much more accessible diagnostic than colonoscopy screening or even mammography,” Bhatia says. “Ultimately, if these tools really are predictive, then we should be able to get many more patients into the system who could benefit from cancer interception or better therapy.”

The research was funded by the Koch Institute Support (core) Grant from the National Cancer Institute, the Marble Center for Cancer Nanomedicine, the Gerstner Family Foundation, the Ludwig Center at MIT, the Koch Institute Frontier Research Program via the Casey and Family Foundation, and the Bridge Project, a partnership between the Koch Institute and the Dana-Farber/Harvard Cancer Center.

© Image: MIT News; iStock