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.

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.

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.

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.

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.

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.

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.

On Nov. 7, a team from the Marble Center for Cancer Nanomedicine at MIT showed a Washington audience several examples of how nanotechnologies developed at the Institute can transform the detection and treatment of cancer and other diseases.

The team was one of 40 innovative groups featured at “American Possibilities: A White House Demo Day.” Technology on view spanned energy, artificial intelligence, climate, and health, highlighting advancements that contribute to building a better future for all Americans.

Participants included President Joe Biden, Biden-Harris administration leaders and White House staff, members of Congress, federal R&D funding agencies, scientists and engineers, academics, students, and science and technology industry innovators. The event holds special significance for MIT as eight years ago, MIT's Computer Science and Artificial Intelligence Laboratory participated in the last iteration of the White House Demo Day under President Barack Obama.

“It was truly inspirational hearing from experts from all across the government, the private sector, and academia touching on so many fields,” said President Biden of the event. “It was a reminder, at least for me, of what I’ve long believed — that America can be defined by a single word... possibilities.”

Launched in 2016, the Marble Center for Cancer Nanomedicine was established at the Koch Institute for Integrative Research at MIT to serve as a hub for miniaturized biomedical technologies, especially those that address grand challenges in cancer detection, treatment, and monitoring. The center convenes Koch Institute faculty members Sangeeta Bhatia, Paula Hammond, Robert Langer, Angela Belcher, Darrell Irvine, and Daniel Anderson to advance nanomedicine, as well as to facilitate collaboration with industry partners, including Alloy Therapeutics, Danaher Corp., Fujifilm, and Sanofi. 

Ana Jaklenec, a principal research scientist at the Koch Institute, highlighted several groundbreaking technologies in vaccines and disease diagnostics and treatment at the event. Jaklenec gave demonstrations from projects from her research group, including novel vaccine formulations capable of releasing a dozen booster doses pulsed over predetermined time points, microneedle vaccine technologies, and nutrient delivery technologies for precise control over microbiome modulation and nutrient absorption.

Jaklenec describes the event as “a wonderful opportunity to meet our government leaders and policymakers and see their passion for curing cancer. But it was especially moving to interact with people representing diverse communities across the United States and hear their excitement for how our technologies could positively impact their communities.”

Jeremy Li, a former MIT postdoc, presented a technology developed in the Belcher laboratory and commercialized by the spinout Cision Vision. The startup is developing a new approach to visualize lymph nodes in real time without any injection or radiation. The shoebox-sized device was also selected as part of Time Magazine’s Best Inventions of 2023 and is currently being used in a dozen hospitals across the United States.

“It was a proud moment for Cision Vision to be part of this event and discuss our recent progress in the field of medical imaging and cancer care,” says Li, who is a co-founder and the CEO of CisionVision. “It was a humbling experience for us to hear directly from patient advocates and cancer survivors at the event. We feel more inspired than ever to bring better solutions for cancer care to patients around the world.”

Other technologies shown at the event included new approaches such as a tortoise-shaped pill designed to enhance the efficacy of oral medicines, a miniature organ-on-a-chip liver device to predict drug toxicity and model liver disease, and a wireless bioelectronic device that provides oxygen for cell therapy applications and for the treatment of chronic disease.

“The feedback from the organizers and the audience at the event has been overwhelmingly positive,” says Tarek Fadel, who led the team’s participation at the event. “Navigating the demonstration space felt like stepping into the future. As a center, we stand poised to engineer transformative tools that will truly make a difference for the future of cancer care.”

Sangeeta Bhatia, the Director of the Marble Center and the John J. and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science, adds: “The showcase of our technologies at the White House Demo Day underscores the transformative impact we aim to achieve in cancer detection and treatment. The event highlights our vision to advance cutting-edge solutions for the benefit of patients and communities worldwide.”

Some Covid-19 vaccines safely and effectively used lipid nanoparticles (LNPs) to deliver messenger RNA to cells. A new MIT study shows that different nanoparticles could be used for a potential Alzheimer’s disease (AD) therapy. In tests in multiple mouse models and with cultured human cells, a newly tailored LNP formulation effectively delivered small interfering RNA (siRNA) to the brain’s microglia immune cells to suppress expression of a protein linked to excessive inflammation in Alzheimer’s disease.

In a prior study, the researchers showed that blocking the consequences of PU.1 protein activity helps to reduce Alzheimer’s disease-related neuroinflammation and pathology. The new open-access results, reported in the journal Advanced Materials, achieves a reduction in inflammation by directly tamping down expression of the Spi1 gene that encodes PU.1. More generally, the new study also demonstrates a new way to deliver RNA to microglia, which have been difficult to target so far.

Study co-senior author Li-Huei Tsai, the Picower professor of neuroscience and director of The Picower Institute for Learning and Memory and Aging Brain Initiative at MIT, says she hypothesized that LNPs might work as a way to bring siRNA into microglia because the cells, which clear waste in the brain, have a strong proclivity to uptake lipid molecules. She discussed this with Robert Langer, the David Koch Institute Professor, who is widely known for his influential work on nanoparticle drug delivery. They decided to test the idea of reducing PU.1 expression with an LNP-delivered siRNA.

“I still remember the day when I asked to meet with Bob to discuss the idea of testing LNPs as a payload to target inflammatory microglia,” says Tsai, a faculty member in the Department of Brain and Cognitive Sciences. “I am very grateful to The JPB Foundation, who supported this idea without any preliminary evidence.”

Langer Lab graduate student Jason Andresen and former Tsai Lab postdoc William Ralvenius led the work and are the study’s co-lead authors. Owen Fenton, a former Langer Lab postdoc who is now an assistant professor at the University of North Carolina’s Eshelman School of Pharmacy, is a co-corresponding author along with Tsai and Langer. Langer is a professor in the departments of Chemical Engineering and Biological Engineering, and the Koch Institute for Integrative Cancer Research.

Perfecting a particle

The simplest way to test whether siRNA could therapeutically suppress PU.1 expression would have been to make use of an already available delivery device, but one of the first discoveries in the study is that none of eight commercially available reagents could safely and effectively transfect cultured human microglia-like cells in the lab.

Instead, the team had to optimize an LNP to do the job. LNPs have four main components; by changing the structures of two of them, and by varying the ratio of lipids to RNA, the researchers were able to come up with seven formulations to try. Importantly, their testing included trying their formulations on cultured microglia that they had induced into an inflammatory state. That state, after all, is the one in which the proposed treatment is needed.

Among the seven candidates, one the team named “MG-LNP” stood out for its especially high delivery efficiency and safety of a test RNA cargo.

What works in a dish sometimes doesn’t work in a living organism, so the team next tested their LNP formulations’ effectiveness and safety in mice. Testing two different methods of injection, into the body or into the cerebrospinal fluid (CSF), they found that injection into the CSF ensured much greater efficacy in targeting microglia without affecting cells in other organs. Among the seven formulations, MG-LNP again proved the most effective at transfecting microglia. Langer said he believes this could potentially open new ways of treating certain brain diseases with nanoparticles someday. 

A targeted therapy

Once they knew MG-LNP could deliver a test cargo to microglia both in human cell cultures and mice, the scientists then tested whether using it to deliver a PU.1-suppressing siRNA could reduce inflammation in microglia. In the cell cultures, a relatively low dose achieved a 42 percent reduction of PU.1 expression (which is good because microglia need at least some PU.1 to live). Indeed, MG-LNP transfection did not cause the cells any harm. It also significantly reduced the transcription of the genes that PU.1 expression increases in microglia, indicating that it can reduce multiple inflammatory markers.

In all these measures, and others, MG-LNP outperformed a commercially available reagent called RNAiMAX that the scientists tested in parallel.

“These findings support the use of MG-LNP-mediated anti-PU.1 siRNA delivery as a potential therapy for neuroinflammatory diseases,” the researchers wrote.

The final set of tests evaluated MG-LNP’s performance delivering the siRNA in two mouse models of inflammation in the brain. In one, mice were exposed to LPS, a molecule that simulates infection and stimulates a systemic inflammation response. In the other model, mice exhibit severe neurodegeneration and inflammation when an enzyme called CDK5 becomes hyperactivated by a protein called p25.

In both models, injection of MG-LNPs carrying the anti-PU.1 siRNA reduced expression of PU.1 and inflammatory markers, much like in the cultured human cells.

“MG-LNP delivery of anti-PU.1 siRNA can potentially be used as an anti-inflammatory therapeutic in mice with systemic inflammation an in the CK-p25 mouse model of AD-like neuroinflammation,” the scientists concluded, calling the results a “proof-of-principle.” More testing will be required before the idea could be tried in human patients.

In addition to Andresen, Ralvenius, Langer, Tsai, and Owen, the paper’s other authors are Margaret Huston, Jay Penney, and Julia Maeve Bonner.

In addition to the The JPB Foundation and The Picower Institute for Learning and Memory, the Robert and Renee Belfer Family, Eduardo Eurnekian, Lester A. Gimpelson, Jay L. and Carroll Miller, the Koch Institute, the Swiss National Science Foundation, and the Alzheimer’s Association provided funding for the study.

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.

On Nov. 7, a team from the Marble Center for Cancer Nanomedicine at MIT showed a Washington audience several examples of how nanotechnologies developed at the Institute can transform the detection and treatment of cancer and other diseases.

The team was one of 40 innovative groups featured at “American Possibilities: A White House Demo Day.” Technology on view spanned energy, artificial intelligence, climate, and health, highlighting advancements that contribute to building a better future for all Americans.

Participants included President Joe Biden, Biden-Harris administration leaders and White House staff, members of Congress, federal R&D funding agencies, scientists and engineers, academics, students, and science and technology industry innovators. The event holds special significance for MIT as eight years ago, MIT's Computer Science and Artificial Intelligence Laboratory participated in the last iteration of the White House Demo Day under President Barack Obama.

“It was truly inspirational hearing from experts from all across the government, the private sector, and academia touching on so many fields,” said President Biden of the event. “It was a reminder, at least for me, of what I’ve long believed — that America can be defined by a single word... possibilities.”

Launched in 2016, the Marble Center for Cancer Nanomedicine was established at the Koch Institute for Integrative Research at MIT to serve as a hub for miniaturized biomedical technologies, especially those that address grand challenges in cancer detection, treatment, and monitoring. The center convenes Koch Institute faculty members Sangeeta Bhatia, Paula Hammond, Robert Langer, Angela Belcher, Darrell Irvine, and Daniel Anderson to advance nanomedicine, as well as to facilitate collaboration with industry partners, including Alloy Therapeutics, Danaher Corp., Fujifilm, and Sanofi. 

Ana Jaklenec, a principal research scientist at the Koch Institute, highlighted several groundbreaking technologies in vaccines and disease diagnostics and treatment at the event. Jaklenec gave demonstrations from projects from her research group, including novel vaccine formulations capable of releasing a dozen booster doses pulsed over predetermined time points, microneedle vaccine technologies, and nutrient delivery technologies for precise control over microbiome modulation and nutrient absorption.

Jaklenec describes the event as “a wonderful opportunity to meet our government leaders and policymakers and see their passion for curing cancer. But it was especially moving to interact with people representing diverse communities across the United States and hear their excitement for how our technologies could positively impact their communities.”

Jeremy Li, a former MIT postdoc, presented a technology developed in the Belcher laboratory and commercialized by the spinout Cision Vision. The startup is developing a new approach to visualize lymph nodes in real time without any injection or radiation. The shoebox-sized device was also selected as part of Time Magazine’s Best Inventions of 2023 and is currently being used in a dozen hospitals across the United States.

“It was a proud moment for Cision Vision to be part of this event and discuss our recent progress in the field of medical imaging and cancer care,” says Li, who is a co-founder and the CEO of CisionVision. “It was a humbling experience for us to hear directly from patient advocates and cancer survivors at the event. We feel more inspired than ever to bring better solutions for cancer care to patients around the world.”

Other technologies shown at the event included new approaches such as a tortoise-shaped pill designed to enhance the efficacy of oral medicines, a miniature organ-on-a-chip liver device to predict drug toxicity and model liver disease, and a wireless bioelectronic device that provides oxygen for cell therapy applications and for the treatment of chronic disease.

“The feedback from the organizers and the audience at the event has been overwhelmingly positive,” says Tarek Fadel, who led the team’s participation at the event. “Navigating the demonstration space felt like stepping into the future. As a center, we stand poised to engineer transformative tools that will truly make a difference for the future of cancer care.”

Sangeeta Bhatia, the Director of the Marble Center and the John J. and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science, adds: “The showcase of our technologies at the White House Demo Day underscores the transformative impact we aim to achieve in cancer detection and treatment. The event highlights our vision to advance cutting-edge solutions for the benefit of patients and communities worldwide.”

Some Covid-19 vaccines safely and effectively used lipid nanoparticles (LNPs) to deliver messenger RNA to cells. A new MIT study shows that different nanoparticles could be used for a potential Alzheimer’s disease (AD) therapy. In tests in multiple mouse models and with cultured human cells, a newly tailored LNP formulation effectively delivered small interfering RNA (siRNA) to the brain’s microglia immune cells to suppress expression of a protein linked to excessive inflammation in Alzheimer’s disease.

In a prior study, the researchers showed that blocking the consequences of PU.1 protein activity helps to reduce Alzheimer’s disease-related neuroinflammation and pathology. The new open-access results, reported in the journal Advanced Materials, achieves a reduction in inflammation by directly tamping down expression of the Spi1 gene that encodes PU.1. More generally, the new study also demonstrates a new way to deliver RNA to microglia, which have been difficult to target so far.

Study co-senior author Li-Huei Tsai, the Picower professor of neuroscience and director of The Picower Institute for Learning and Memory and Aging Brain Initiative at MIT, says she hypothesized that LNPs might work as a way to bring siRNA into microglia because the cells, which clear waste in the brain, have a strong proclivity to uptake lipid molecules. She discussed this with Robert Langer, the David Koch Institute Professor, who is widely known for his influential work on nanoparticle drug delivery. They decided to test the idea of reducing PU.1 expression with an LNP-delivered siRNA.

“I still remember the day when I asked to meet with Bob to discuss the idea of testing LNPs as a payload to target inflammatory microglia,” says Tsai, a faculty member in the Department of Brain and Cognitive Sciences. “I am very grateful to The JPB Foundation, who supported this idea without any preliminary evidence.”

Langer Lab graduate student Jason Andresen and former Tsai Lab postdoc William Ralvenius led the work and are the study’s co-lead authors. Owen Fenton, a former Langer Lab postdoc who is now an assistant professor at the University of North Carolina’s Eshelman School of Pharmacy, is a co-corresponding author along with Tsai and Langer. Langer is a professor in the departments of Chemical Engineering and Biological Engineering, and the Koch Institute for Integrative Cancer Research.

Perfecting a particle

The simplest way to test whether siRNA could therapeutically suppress PU.1 expression would have been to make use of an already available delivery device, but one of the first discoveries in the study is that none of eight commercially available reagents could safely and effectively transfect cultured human microglia-like cells in the lab.

Instead, the team had to optimize an LNP to do the job. LNPs have four main components; by changing the structures of two of them, and by varying the ratio of lipids to RNA, the researchers were able to come up with seven formulations to try. Importantly, their testing included trying their formulations on cultured microglia that they had induced into an inflammatory state. That state, after all, is the one in which the proposed treatment is needed.

Among the seven candidates, one the team named “MG-LNP” stood out for its especially high delivery efficiency and safety of a test RNA cargo.

What works in a dish sometimes doesn’t work in a living organism, so the team next tested their LNP formulations’ effectiveness and safety in mice. Testing two different methods of injection, into the body or into the cerebrospinal fluid (CSF), they found that injection into the CSF ensured much greater efficacy in targeting microglia without affecting cells in other organs. Among the seven formulations, MG-LNP again proved the most effective at transfecting microglia. Langer said he believes this could potentially open new ways of treating certain brain diseases with nanoparticles someday. 

A targeted therapy

Once they knew MG-LNP could deliver a test cargo to microglia both in human cell cultures and mice, the scientists then tested whether using it to deliver a PU.1-suppressing siRNA could reduce inflammation in microglia. In the cell cultures, a relatively low dose achieved a 42 percent reduction of PU.1 expression (which is good because microglia need at least some PU.1 to live). Indeed, MG-LNP transfection did not cause the cells any harm. It also significantly reduced the transcription of the genes that PU.1 expression increases in microglia, indicating that it can reduce multiple inflammatory markers.

In all these measures, and others, MG-LNP outperformed a commercially available reagent called RNAiMAX that the scientists tested in parallel.

“These findings support the use of MG-LNP-mediated anti-PU.1 siRNA delivery as a potential therapy for neuroinflammatory diseases,” the researchers wrote.

The final set of tests evaluated MG-LNP’s performance delivering the siRNA in two mouse models of inflammation in the brain. In one, mice were exposed to LPS, a molecule that simulates infection and stimulates a systemic inflammation response. In the other model, mice exhibit severe neurodegeneration and inflammation when an enzyme called CDK5 becomes hyperactivated by a protein called p25.

In both models, injection of MG-LNPs carrying the anti-PU.1 siRNA reduced expression of PU.1 and inflammatory markers, much like in the cultured human cells.

“MG-LNP delivery of anti-PU.1 siRNA can potentially be used as an anti-inflammatory therapeutic in mice with systemic inflammation an in the CK-p25 mouse model of AD-like neuroinflammation,” the scientists concluded, calling the results a “proof-of-principle.” More testing will be required before the idea could be tried in human patients.

In addition to Andresen, Ralvenius, Langer, Tsai, and Owen, the paper’s other authors are Margaret Huston, Jay Penney, and Julia Maeve Bonner.

In addition to the The JPB Foundation and The Picower Institute for Learning and Memory, the Robert and Renee Belfer Family, Eduardo Eurnekian, Lester A. Gimpelson, Jay L. and Carroll Miller, the Koch Institute, the Swiss National Science Foundation, and the Alzheimer’s Association provided funding for the study.

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.

On Nov. 7, a team from the Marble Center for Cancer Nanomedicine at MIT showed a Washington audience several examples of how nanotechnologies developed at the Institute can transform the detection and treatment of cancer and other diseases.

The team was one of 40 innovative groups featured at “American Possibilities: A White House Demo Day.” Technology on view spanned energy, artificial intelligence, climate, and health, highlighting advancements that contribute to building a better future for all Americans.

Participants included President Joe Biden, Biden-Harris administration leaders and White House staff, members of Congress, federal R&D funding agencies, scientists and engineers, academics, students, and science and technology industry innovators. The event holds special significance for MIT as eight years ago, MIT's Computer Science and Artificial Intelligence Laboratory participated in the last iteration of the White House Demo Day under President Barack Obama.

“It was truly inspirational hearing from experts from all across the government, the private sector, and academia touching on so many fields,” said President Biden of the event. “It was a reminder, at least for me, of what I’ve long believed — that America can be defined by a single word... possibilities.”

Launched in 2016, the Marble Center for Cancer Nanomedicine was established at the Koch Institute for Integrative Research at MIT to serve as a hub for miniaturized biomedical technologies, especially those that address grand challenges in cancer detection, treatment, and monitoring. The center convenes Koch Institute faculty members Sangeeta Bhatia, Paula Hammond, Robert Langer, Angela Belcher, Darrell Irvine, and Daniel Anderson to advance nanomedicine, as well as to facilitate collaboration with industry partners, including Alloy Therapeutics, Danaher Corp., Fujifilm, and Sanofi. 

Ana Jaklenec, a principal research scientist at the Koch Institute, highlighted several groundbreaking technologies in vaccines and disease diagnostics and treatment at the event. Jaklenec gave demonstrations from projects from her research group, including novel vaccine formulations capable of releasing a dozen booster doses pulsed over predetermined time points, microneedle vaccine technologies, and nutrient delivery technologies for precise control over microbiome modulation and nutrient absorption.

Jaklenec describes the event as “a wonderful opportunity to meet our government leaders and policymakers and see their passion for curing cancer. But it was especially moving to interact with people representing diverse communities across the United States and hear their excitement for how our technologies could positively impact their communities.”

Jeremy Li, a former MIT postdoc, presented a technology developed in the Belcher laboratory and commercialized by the spinout Cision Vision. The startup is developing a new approach to visualize lymph nodes in real time without any injection or radiation. The shoebox-sized device was also selected as part of Time Magazine’s Best Inventions of 2023 and is currently being used in a dozen hospitals across the United States.

“It was a proud moment for Cision Vision to be part of this event and discuss our recent progress in the field of medical imaging and cancer care,” says Li, who is a co-founder and the CEO of CisionVision. “It was a humbling experience for us to hear directly from patient advocates and cancer survivors at the event. We feel more inspired than ever to bring better solutions for cancer care to patients around the world.”

Other technologies shown at the event included new approaches such as a tortoise-shaped pill designed to enhance the efficacy of oral medicines, a miniature organ-on-a-chip liver device to predict drug toxicity and model liver disease, and a wireless bioelectronic device that provides oxygen for cell therapy applications and for the treatment of chronic disease.

“The feedback from the organizers and the audience at the event has been overwhelmingly positive,” says Tarek Fadel, who led the team’s participation at the event. “Navigating the demonstration space felt like stepping into the future. As a center, we stand poised to engineer transformative tools that will truly make a difference for the future of cancer care.”

Sangeeta Bhatia, the Director of the Marble Center and the John J. and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science, adds: “The showcase of our technologies at the White House Demo Day underscores the transformative impact we aim to achieve in cancer detection and treatment. The event highlights our vision to advance cutting-edge solutions for the benefit of patients and communities worldwide.”

Some Covid-19 vaccines safely and effectively used lipid nanoparticles (LNPs) to deliver messenger RNA to cells. A new MIT study shows that different nanoparticles could be used for a potential Alzheimer’s disease (AD) therapy. In tests in multiple mouse models and with cultured human cells, a newly tailored LNP formulation effectively delivered small interfering RNA (siRNA) to the brain’s microglia immune cells to suppress expression of a protein linked to excessive inflammation in Alzheimer’s disease.

In a prior study, the researchers showed that blocking the consequences of PU.1 protein activity helps to reduce Alzheimer’s disease-related neuroinflammation and pathology. The new open-access results, reported in the journal Advanced Materials, achieves a reduction in inflammation by directly tamping down expression of the Spi1 gene that encodes PU.1. More generally, the new study also demonstrates a new way to deliver RNA to microglia, which have been difficult to target so far.

Study co-senior author Li-Huei Tsai, the Picower professor of neuroscience and director of The Picower Institute for Learning and Memory and Aging Brain Initiative at MIT, says she hypothesized that LNPs might work as a way to bring siRNA into microglia because the cells, which clear waste in the brain, have a strong proclivity to uptake lipid molecules. She discussed this with Robert Langer, the David Koch Institute Professor, who is widely known for his influential work on nanoparticle drug delivery. They decided to test the idea of reducing PU.1 expression with an LNP-delivered siRNA.

“I still remember the day when I asked to meet with Bob to discuss the idea of testing LNPs as a payload to target inflammatory microglia,” says Tsai, a faculty member in the Department of Brain and Cognitive Sciences. “I am very grateful to The JPB Foundation, who supported this idea without any preliminary evidence.”

Langer Lab graduate student Jason Andresen and former Tsai Lab postdoc William Ralvenius led the work and are the study’s co-lead authors. Owen Fenton, a former Langer Lab postdoc who is now an assistant professor at the University of North Carolina’s Eshelman School of Pharmacy, is a co-corresponding author along with Tsai and Langer. Langer is a professor in the departments of Chemical Engineering and Biological Engineering, and the Koch Institute for Integrative Cancer Research.

Perfecting a particle

The simplest way to test whether siRNA could therapeutically suppress PU.1 expression would have been to make use of an already available delivery device, but one of the first discoveries in the study is that none of eight commercially available reagents could safely and effectively transfect cultured human microglia-like cells in the lab.

Instead, the team had to optimize an LNP to do the job. LNPs have four main components; by changing the structures of two of them, and by varying the ratio of lipids to RNA, the researchers were able to come up with seven formulations to try. Importantly, their testing included trying their formulations on cultured microglia that they had induced into an inflammatory state. That state, after all, is the one in which the proposed treatment is needed.

Among the seven candidates, one the team named “MG-LNP” stood out for its especially high delivery efficiency and safety of a test RNA cargo.

What works in a dish sometimes doesn’t work in a living organism, so the team next tested their LNP formulations’ effectiveness and safety in mice. Testing two different methods of injection, into the body or into the cerebrospinal fluid (CSF), they found that injection into the CSF ensured much greater efficacy in targeting microglia without affecting cells in other organs. Among the seven formulations, MG-LNP again proved the most effective at transfecting microglia. Langer said he believes this could potentially open new ways of treating certain brain diseases with nanoparticles someday. 

A targeted therapy

Once they knew MG-LNP could deliver a test cargo to microglia both in human cell cultures and mice, the scientists then tested whether using it to deliver a PU.1-suppressing siRNA could reduce inflammation in microglia. In the cell cultures, a relatively low dose achieved a 42 percent reduction of PU.1 expression (which is good because microglia need at least some PU.1 to live). Indeed, MG-LNP transfection did not cause the cells any harm. It also significantly reduced the transcription of the genes that PU.1 expression increases in microglia, indicating that it can reduce multiple inflammatory markers.

In all these measures, and others, MG-LNP outperformed a commercially available reagent called RNAiMAX that the scientists tested in parallel.

“These findings support the use of MG-LNP-mediated anti-PU.1 siRNA delivery as a potential therapy for neuroinflammatory diseases,” the researchers wrote.

The final set of tests evaluated MG-LNP’s performance delivering the siRNA in two mouse models of inflammation in the brain. In one, mice were exposed to LPS, a molecule that simulates infection and stimulates a systemic inflammation response. In the other model, mice exhibit severe neurodegeneration and inflammation when an enzyme called CDK5 becomes hyperactivated by a protein called p25.

In both models, injection of MG-LNPs carrying the anti-PU.1 siRNA reduced expression of PU.1 and inflammatory markers, much like in the cultured human cells.

“MG-LNP delivery of anti-PU.1 siRNA can potentially be used as an anti-inflammatory therapeutic in mice with systemic inflammation an in the CK-p25 mouse model of AD-like neuroinflammation,” the scientists concluded, calling the results a “proof-of-principle.” More testing will be required before the idea could be tried in human patients.

In addition to Andresen, Ralvenius, Langer, Tsai, and Owen, the paper’s other authors are Margaret Huston, Jay Penney, and Julia Maeve Bonner.

In addition to the The JPB Foundation and The Picower Institute for Learning and Memory, the Robert and Renee Belfer Family, Eduardo Eurnekian, Lester A. Gimpelson, Jay L. and Carroll Miller, the Koch Institute, the Swiss National Science Foundation, and the Alzheimer’s Association provided funding for the study.

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.

On Nov. 7, a team from the Marble Center for Cancer Nanomedicine at MIT showed a Washington audience several examples of how nanotechnologies developed at the Institute can transform the detection and treatment of cancer and other diseases.

The team was one of 40 innovative groups featured at “American Possibilities: A White House Demo Day.” Technology on view spanned energy, artificial intelligence, climate, and health, highlighting advancements that contribute to building a better future for all Americans.

Participants included President Joe Biden, Biden-Harris administration leaders and White House staff, members of Congress, federal R&D funding agencies, scientists and engineers, academics, students, and science and technology industry innovators. The event holds special significance for MIT as eight years ago, MIT's Computer Science and Artificial Intelligence Laboratory participated in the last iteration of the White House Demo Day under President Barack Obama.

“It was truly inspirational hearing from experts from all across the government, the private sector, and academia touching on so many fields,” said President Biden of the event. “It was a reminder, at least for me, of what I’ve long believed — that America can be defined by a single word... possibilities.”

Launched in 2016, the Marble Center for Cancer Nanomedicine was established at the Koch Institute for Integrative Research at MIT to serve as a hub for miniaturized biomedical technologies, especially those that address grand challenges in cancer detection, treatment, and monitoring. The center convenes Koch Institute faculty members Sangeeta Bhatia, Paula Hammond, Robert Langer, Angela Belcher, Darrell Irvine, and Daniel Anderson to advance nanomedicine, as well as to facilitate collaboration with industry partners, including Alloy Therapeutics, Danaher Corp., Fujifilm, and Sanofi. 

Ana Jaklenec, a principal research scientist at the Koch Institute, highlighted several groundbreaking technologies in vaccines and disease diagnostics and treatment at the event. Jaklenec gave demonstrations from projects from her research group, including novel vaccine formulations capable of releasing a dozen booster doses pulsed over predetermined time points, microneedle vaccine technologies, and nutrient delivery technologies for precise control over microbiome modulation and nutrient absorption.

Jaklenec describes the event as “a wonderful opportunity to meet our government leaders and policymakers and see their passion for curing cancer. But it was especially moving to interact with people representing diverse communities across the United States and hear their excitement for how our technologies could positively impact their communities.”

Jeremy Li, a former MIT postdoc, presented a technology developed in the Belcher laboratory and commercialized by the spinout Cision Vision. The startup is developing a new approach to visualize lymph nodes in real time without any injection or radiation. The shoebox-sized device was also selected as part of Time Magazine’s Best Inventions of 2023 and is currently being used in a dozen hospitals across the United States.

“It was a proud moment for Cision Vision to be part of this event and discuss our recent progress in the field of medical imaging and cancer care,” says Li, who is a co-founder and the CEO of CisionVision. “It was a humbling experience for us to hear directly from patient advocates and cancer survivors at the event. We feel more inspired than ever to bring better solutions for cancer care to patients around the world.”

Other technologies shown at the event included new approaches such as a tortoise-shaped pill designed to enhance the efficacy of oral medicines, a miniature organ-on-a-chip liver device to predict drug toxicity and model liver disease, and a wireless bioelectronic device that provides oxygen for cell therapy applications and for the treatment of chronic disease.

“The feedback from the organizers and the audience at the event has been overwhelmingly positive,” says Tarek Fadel, who led the team’s participation at the event. “Navigating the demonstration space felt like stepping into the future. As a center, we stand poised to engineer transformative tools that will truly make a difference for the future of cancer care.”

Sangeeta Bhatia, the Director of the Marble Center and the John J. and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science, adds: “The showcase of our technologies at the White House Demo Day underscores the transformative impact we aim to achieve in cancer detection and treatment. The event highlights our vision to advance cutting-edge solutions for the benefit of patients and communities worldwide.”

Some Covid-19 vaccines safely and effectively used lipid nanoparticles (LNPs) to deliver messenger RNA to cells. A new MIT study shows that different nanoparticles could be used for a potential Alzheimer’s disease (AD) therapy. In tests in multiple mouse models and with cultured human cells, a newly tailored LNP formulation effectively delivered small interfering RNA (siRNA) to the brain’s microglia immune cells to suppress expression of a protein linked to excessive inflammation in Alzheimer’s disease.

In a prior study, the researchers showed that blocking the consequences of PU.1 protein activity helps to reduce Alzheimer’s disease-related neuroinflammation and pathology. The new open-access results, reported in the journal Advanced Materials, achieves a reduction in inflammation by directly tamping down expression of the Spi1 gene that encodes PU.1. More generally, the new study also demonstrates a new way to deliver RNA to microglia, which have been difficult to target so far.

Study co-senior author Li-Huei Tsai, the Picower professor of neuroscience and director of The Picower Institute for Learning and Memory and Aging Brain Initiative at MIT, says she hypothesized that LNPs might work as a way to bring siRNA into microglia because the cells, which clear waste in the brain, have a strong proclivity to uptake lipid molecules. She discussed this with Robert Langer, the David Koch Institute Professor, who is widely known for his influential work on nanoparticle drug delivery. They decided to test the idea of reducing PU.1 expression with an LNP-delivered siRNA.

“I still remember the day when I asked to meet with Bob to discuss the idea of testing LNPs as a payload to target inflammatory microglia,” says Tsai, a faculty member in the Department of Brain and Cognitive Sciences. “I am very grateful to The JPB Foundation, who supported this idea without any preliminary evidence.”

Langer Lab graduate student Jason Andresen and former Tsai Lab postdoc William Ralvenius led the work and are the study’s co-lead authors. Owen Fenton, a former Langer Lab postdoc who is now an assistant professor at the University of North Carolina’s Eshelman School of Pharmacy, is a co-corresponding author along with Tsai and Langer. Langer is a professor in the departments of Chemical Engineering and Biological Engineering, and the Koch Institute for Integrative Cancer Research.

Perfecting a particle

The simplest way to test whether siRNA could therapeutically suppress PU.1 expression would have been to make use of an already available delivery device, but one of the first discoveries in the study is that none of eight commercially available reagents could safely and effectively transfect cultured human microglia-like cells in the lab.

Instead, the team had to optimize an LNP to do the job. LNPs have four main components; by changing the structures of two of them, and by varying the ratio of lipids to RNA, the researchers were able to come up with seven formulations to try. Importantly, their testing included trying their formulations on cultured microglia that they had induced into an inflammatory state. That state, after all, is the one in which the proposed treatment is needed.

Among the seven candidates, one the team named “MG-LNP” stood out for its especially high delivery efficiency and safety of a test RNA cargo.

What works in a dish sometimes doesn’t work in a living organism, so the team next tested their LNP formulations’ effectiveness and safety in mice. Testing two different methods of injection, into the body or into the cerebrospinal fluid (CSF), they found that injection into the CSF ensured much greater efficacy in targeting microglia without affecting cells in other organs. Among the seven formulations, MG-LNP again proved the most effective at transfecting microglia. Langer said he believes this could potentially open new ways of treating certain brain diseases with nanoparticles someday. 

A targeted therapy

Once they knew MG-LNP could deliver a test cargo to microglia both in human cell cultures and mice, the scientists then tested whether using it to deliver a PU.1-suppressing siRNA could reduce inflammation in microglia. In the cell cultures, a relatively low dose achieved a 42 percent reduction of PU.1 expression (which is good because microglia need at least some PU.1 to live). Indeed, MG-LNP transfection did not cause the cells any harm. It also significantly reduced the transcription of the genes that PU.1 expression increases in microglia, indicating that it can reduce multiple inflammatory markers.

In all these measures, and others, MG-LNP outperformed a commercially available reagent called RNAiMAX that the scientists tested in parallel.

“These findings support the use of MG-LNP-mediated anti-PU.1 siRNA delivery as a potential therapy for neuroinflammatory diseases,” the researchers wrote.

The final set of tests evaluated MG-LNP’s performance delivering the siRNA in two mouse models of inflammation in the brain. In one, mice were exposed to LPS, a molecule that simulates infection and stimulates a systemic inflammation response. In the other model, mice exhibit severe neurodegeneration and inflammation when an enzyme called CDK5 becomes hyperactivated by a protein called p25.

In both models, injection of MG-LNPs carrying the anti-PU.1 siRNA reduced expression of PU.1 and inflammatory markers, much like in the cultured human cells.

“MG-LNP delivery of anti-PU.1 siRNA can potentially be used as an anti-inflammatory therapeutic in mice with systemic inflammation an in the CK-p25 mouse model of AD-like neuroinflammation,” the scientists concluded, calling the results a “proof-of-principle.” More testing will be required before the idea could be tried in human patients.

In addition to Andresen, Ralvenius, Langer, Tsai, and Owen, the paper’s other authors are Margaret Huston, Jay Penney, and Julia Maeve Bonner.

In addition to the The JPB Foundation and The Picower Institute for Learning and Memory, the Robert and Renee Belfer Family, Eduardo Eurnekian, Lester A. Gimpelson, Jay L. and Carroll Miller, the Koch Institute, the Swiss National Science Foundation, and the Alzheimer’s Association provided funding for the study.

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.

On Nov. 7, a team from the Marble Center for Cancer Nanomedicine at MIT showed a Washington audience several examples of how nanotechnologies developed at the Institute can transform the detection and treatment of cancer and other diseases.

The team was one of 40 innovative groups featured at “American Possibilities: A White House Demo Day.” Technology on view spanned energy, artificial intelligence, climate, and health, highlighting advancements that contribute to building a better future for all Americans.

Participants included President Joe Biden, Biden-Harris administration leaders and White House staff, members of Congress, federal R&D funding agencies, scientists and engineers, academics, students, and science and technology industry innovators. The event holds special significance for MIT as eight years ago, MIT's Computer Science and Artificial Intelligence Laboratory participated in the last iteration of the White House Demo Day under President Barack Obama.

“It was truly inspirational hearing from experts from all across the government, the private sector, and academia touching on so many fields,” said President Biden of the event. “It was a reminder, at least for me, of what I’ve long believed — that America can be defined by a single word... possibilities.”

Launched in 2016, the Marble Center for Cancer Nanomedicine was established at the Koch Institute for Integrative Research at MIT to serve as a hub for miniaturized biomedical technologies, especially those that address grand challenges in cancer detection, treatment, and monitoring. The center convenes Koch Institute faculty members Sangeeta Bhatia, Paula Hammond, Robert Langer, Angela Belcher, Darrell Irvine, and Daniel Anderson to advance nanomedicine, as well as to facilitate collaboration with industry partners, including Alloy Therapeutics, Danaher Corp., Fujifilm, and Sanofi. 

Ana Jaklenec, a principal research scientist at the Koch Institute, highlighted several groundbreaking technologies in vaccines and disease diagnostics and treatment at the event. Jaklenec gave demonstrations from projects from her research group, including novel vaccine formulations capable of releasing a dozen booster doses pulsed over predetermined time points, microneedle vaccine technologies, and nutrient delivery technologies for precise control over microbiome modulation and nutrient absorption.

Jaklenec describes the event as “a wonderful opportunity to meet our government leaders and policymakers and see their passion for curing cancer. But it was especially moving to interact with people representing diverse communities across the United States and hear their excitement for how our technologies could positively impact their communities.”

Jeremy Li, a former MIT postdoc, presented a technology developed in the Belcher laboratory and commercialized by the spinout Cision Vision. The startup is developing a new approach to visualize lymph nodes in real time without any injection or radiation. The shoebox-sized device was also selected as part of Time Magazine’s Best Inventions of 2023 and is currently being used in a dozen hospitals across the United States.

“It was a proud moment for Cision Vision to be part of this event and discuss our recent progress in the field of medical imaging and cancer care,” says Li, who is a co-founder and the CEO of CisionVision. “It was a humbling experience for us to hear directly from patient advocates and cancer survivors at the event. We feel more inspired than ever to bring better solutions for cancer care to patients around the world.”

Other technologies shown at the event included new approaches such as a tortoise-shaped pill designed to enhance the efficacy of oral medicines, a miniature organ-on-a-chip liver device to predict drug toxicity and model liver disease, and a wireless bioelectronic device that provides oxygen for cell therapy applications and for the treatment of chronic disease.

“The feedback from the organizers and the audience at the event has been overwhelmingly positive,” says Tarek Fadel, who led the team’s participation at the event. “Navigating the demonstration space felt like stepping into the future. As a center, we stand poised to engineer transformative tools that will truly make a difference for the future of cancer care.”

Sangeeta Bhatia, the Director of the Marble Center and the John J. and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science, adds: “The showcase of our technologies at the White House Demo Day underscores the transformative impact we aim to achieve in cancer detection and treatment. The event highlights our vision to advance cutting-edge solutions for the benefit of patients and communities worldwide.”

Some Covid-19 vaccines safely and effectively used lipid nanoparticles (LNPs) to deliver messenger RNA to cells. A new MIT study shows that different nanoparticles could be used for a potential Alzheimer’s disease (AD) therapy. In tests in multiple mouse models and with cultured human cells, a newly tailored LNP formulation effectively delivered small interfering RNA (siRNA) to the brain’s microglia immune cells to suppress expression of a protein linked to excessive inflammation in Alzheimer’s disease.

In a prior study, the researchers showed that blocking the consequences of PU.1 protein activity helps to reduce Alzheimer’s disease-related neuroinflammation and pathology. The new open-access results, reported in the journal Advanced Materials, achieves a reduction in inflammation by directly tamping down expression of the Spi1 gene that encodes PU.1. More generally, the new study also demonstrates a new way to deliver RNA to microglia, which have been difficult to target so far.

Study co-senior author Li-Huei Tsai, the Picower professor of neuroscience and director of The Picower Institute for Learning and Memory and Aging Brain Initiative at MIT, says she hypothesized that LNPs might work as a way to bring siRNA into microglia because the cells, which clear waste in the brain, have a strong proclivity to uptake lipid molecules. She discussed this with Robert Langer, the David Koch Institute Professor, who is widely known for his influential work on nanoparticle drug delivery. They decided to test the idea of reducing PU.1 expression with an LNP-delivered siRNA.

“I still remember the day when I asked to meet with Bob to discuss the idea of testing LNPs as a payload to target inflammatory microglia,” says Tsai, a faculty member in the Department of Brain and Cognitive Sciences. “I am very grateful to The JPB Foundation, who supported this idea without any preliminary evidence.”

Langer Lab graduate student Jason Andresen and former Tsai Lab postdoc William Ralvenius led the work and are the study’s co-lead authors. Owen Fenton, a former Langer Lab postdoc who is now an assistant professor at the University of North Carolina’s Eshelman School of Pharmacy, is a co-corresponding author along with Tsai and Langer. Langer is a professor in the departments of Chemical Engineering and Biological Engineering, and the Koch Institute for Integrative Cancer Research.

Perfecting a particle

The simplest way to test whether siRNA could therapeutically suppress PU.1 expression would have been to make use of an already available delivery device, but one of the first discoveries in the study is that none of eight commercially available reagents could safely and effectively transfect cultured human microglia-like cells in the lab.

Instead, the team had to optimize an LNP to do the job. LNPs have four main components; by changing the structures of two of them, and by varying the ratio of lipids to RNA, the researchers were able to come up with seven formulations to try. Importantly, their testing included trying their formulations on cultured microglia that they had induced into an inflammatory state. That state, after all, is the one in which the proposed treatment is needed.

Among the seven candidates, one the team named “MG-LNP” stood out for its especially high delivery efficiency and safety of a test RNA cargo.

What works in a dish sometimes doesn’t work in a living organism, so the team next tested their LNP formulations’ effectiveness and safety in mice. Testing two different methods of injection, into the body or into the cerebrospinal fluid (CSF), they found that injection into the CSF ensured much greater efficacy in targeting microglia without affecting cells in other organs. Among the seven formulations, MG-LNP again proved the most effective at transfecting microglia. Langer said he believes this could potentially open new ways of treating certain brain diseases with nanoparticles someday. 

A targeted therapy

Once they knew MG-LNP could deliver a test cargo to microglia both in human cell cultures and mice, the scientists then tested whether using it to deliver a PU.1-suppressing siRNA could reduce inflammation in microglia. In the cell cultures, a relatively low dose achieved a 42 percent reduction of PU.1 expression (which is good because microglia need at least some PU.1 to live). Indeed, MG-LNP transfection did not cause the cells any harm. It also significantly reduced the transcription of the genes that PU.1 expression increases in microglia, indicating that it can reduce multiple inflammatory markers.

In all these measures, and others, MG-LNP outperformed a commercially available reagent called RNAiMAX that the scientists tested in parallel.

“These findings support the use of MG-LNP-mediated anti-PU.1 siRNA delivery as a potential therapy for neuroinflammatory diseases,” the researchers wrote.

The final set of tests evaluated MG-LNP’s performance delivering the siRNA in two mouse models of inflammation in the brain. In one, mice were exposed to LPS, a molecule that simulates infection and stimulates a systemic inflammation response. In the other model, mice exhibit severe neurodegeneration and inflammation when an enzyme called CDK5 becomes hyperactivated by a protein called p25.

In both models, injection of MG-LNPs carrying the anti-PU.1 siRNA reduced expression of PU.1 and inflammatory markers, much like in the cultured human cells.

“MG-LNP delivery of anti-PU.1 siRNA can potentially be used as an anti-inflammatory therapeutic in mice with systemic inflammation an in the CK-p25 mouse model of AD-like neuroinflammation,” the scientists concluded, calling the results a “proof-of-principle.” More testing will be required before the idea could be tried in human patients.

In addition to Andresen, Ralvenius, Langer, Tsai, and Owen, the paper’s other authors are Margaret Huston, Jay Penney, and Julia Maeve Bonner.

In addition to the The JPB Foundation and The Picower Institute for Learning and Memory, the Robert and Renee Belfer Family, Eduardo Eurnekian, Lester A. Gimpelson, Jay L. and Carroll Miller, the Koch Institute, the Swiss National Science Foundation, and the Alzheimer’s Association provided funding for the study.

Many of the most promising new pharmaceuticals coming along in the drug development pathway are hydrophobic by nature — that is, they repel water, and are thus hard to dissolve in order to make them available to the body. But now, researchers at MIT have found a more efficient way of processing and delivering these drugs that could make them far more effective.

The new method, which involves initially processing the drugs in a liquid solution rather than in solid form, is reported in a paper in the Dec. 15 print issue of the journal Advanced Healthcare Materials, written by MIT graduate student Lucas Attia, recent graduate Liang-Hsun Chen PhD ’22, and professor of chemical engineering Patrick Doyle.

Currently, much drug processing is done through a long series of sequential steps, Doyle explains. “We think we can streamline the process, but also get better products, by combining these steps and leveraging our understanding of soft matter and self-assembly processes,” he says.

Attia adds that “a lot of small-molecule active ingredients are hydrophobic, so they don’t like being in water and they have very poor dissolution in water, which leads to their poor bioavailability.” Giving such drugs orally, which patients prefer over injections, presents real challenges in getting the material into the patient’s bloodstream. Up to 90 percent of the candidate drug molecules being developed by pharmaceutical companies actually are hydrophobic, he says, “so this is relevant to a large class of potential drug molecules.”

Another advantage of the new process, he says, is that it should make it easier to combine multiple different drugs in a single pill. “For different types of diseases where you’re taking multiple drugs at the same time, this kind of product can be very important in improving patient compliance,” he adds — only having to take one pill instead of a handful makes it much more likely that patients will keep up with their medications. “That’s actually a big issue with these chronic illnesses where patients are on very challenging pill regimes, so combination products have been shown to help a lot.”

One key to the new process is the use of a hydrogel — a sort of sponge-like gel material that can retain water and hold molecules in place. Present processes for making hydrophobic materials more bioavailable involve mechanically grinding the crystals down to smaller size, which makes them dissolve more readily, but this process adds time and expense to the manufacturing process, provides little control over the size distribution of the particles, and can actually damage some more delicate drug molecules.

Instead, the new process involves dissolving the drug in a carrier solution, then generating tiny nanodroplets of this carrier dispersed throughout a polymer solution — a material called a nanoemulsion. Then, this nanoemulsion is squeezed through a syringe and gelled into a hydrogel. The hydrogel holds the droplets in place as the carrier evaporates, leaving behind drug nanocrystals. This approach allows precise control over the final crystal size. The hydrogel, by keeping the droplets in place as they dry, prevents them from simply merging together to form lumpy agglomerations of different sizes. Without the hydrogel the droplets would merge randomly, and “you’d get a mess,” Doyle says. Instead, the new process leaves a batch of perfectly uniform nanoparticles. “That’s a very unique, novel way that our group has invented, to do this sort of crystallization and maintain the nano size,” he says.

The new process yields a two-part package: a core, which contains the active molecules, surrounded by a shell, also made of hydrogel, which can control the timing between ingestion of the pill and the release of its contents into the body.

“We showed that we can get very precise control over the drug release, both in terms of delay and rate,” says Doyle, who is the Robert T. Haslam Professor of Chemical Engineering and Singapore Research Professor. For example, if a drug is targeting disease in the lower intestine or colon, “we can control how long until the drug release starts, and then we also get very fast release once it begins.” Drugs formulated the conventional way with mechanical nanomilling, he says, “would have a slow drug release.”

This process, Attia says, “is the first approach that can form core-shell composite particles and structure drugs in distinct polymeric layers in a single processing step.”

The next steps in developing the process will be to test the system on a wide variety of drug molecules, beyond the two representative examples that were tested so far, Doyle says. Although they have reason to believe the process is generalizable, he says, “the proof is in the pudding — having the data in hand.”

The dripping process they use, he says, “can be scalable, but there’s a lot of details to be worked out.” But because all of the materials they are working with have been chosen as ones that are already recognized as safe for medical use, the approval process should be straightforward, he says. “It could be implemented in a few years. … We’re not worrying about all those typical safety hurdles that I think other novel formulations have to go through, which can be very expensive.”

The work received support from the U.S. Department of Energy.

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.

On Nov. 7, a team from the Marble Center for Cancer Nanomedicine at MIT showed a Washington audience several examples of how nanotechnologies developed at the Institute can transform the detection and treatment of cancer and other diseases.

The team was one of 40 innovative groups featured at “American Possibilities: A White House Demo Day.” Technology on view spanned energy, artificial intelligence, climate, and health, highlighting advancements that contribute to building a better future for all Americans.

Participants included President Joe Biden, Biden-Harris administration leaders and White House staff, members of Congress, federal R&D funding agencies, scientists and engineers, academics, students, and science and technology industry innovators. The event holds special significance for MIT as eight years ago, MIT's Computer Science and Artificial Intelligence Laboratory participated in the last iteration of the White House Demo Day under President Barack Obama.

“It was truly inspirational hearing from experts from all across the government, the private sector, and academia touching on so many fields,” said President Biden of the event. “It was a reminder, at least for me, of what I’ve long believed — that America can be defined by a single word... possibilities.”

Launched in 2016, the Marble Center for Cancer Nanomedicine was established at the Koch Institute for Integrative Research at MIT to serve as a hub for miniaturized biomedical technologies, especially those that address grand challenges in cancer detection, treatment, and monitoring. The center convenes Koch Institute faculty members Sangeeta Bhatia, Paula Hammond, Robert Langer, Angela Belcher, Darrell Irvine, and Daniel Anderson to advance nanomedicine, as well as to facilitate collaboration with industry partners, including Alloy Therapeutics, Danaher Corp., Fujifilm, and Sanofi. 

Ana Jaklenec, a principal research scientist at the Koch Institute, highlighted several groundbreaking technologies in vaccines and disease diagnostics and treatment at the event. Jaklenec gave demonstrations from projects from her research group, including novel vaccine formulations capable of releasing a dozen booster doses pulsed over predetermined time points, microneedle vaccine technologies, and nutrient delivery technologies for precise control over microbiome modulation and nutrient absorption.

Jaklenec describes the event as “a wonderful opportunity to meet our government leaders and policymakers and see their passion for curing cancer. But it was especially moving to interact with people representing diverse communities across the United States and hear their excitement for how our technologies could positively impact their communities.”

Jeremy Li, a former MIT postdoc, presented a technology developed in the Belcher laboratory and commercialized by the spinout Cision Vision. The startup is developing a new approach to visualize lymph nodes in real time without any injection or radiation. The shoebox-sized device was also selected as part of Time Magazine’s Best Inventions of 2023 and is currently being used in a dozen hospitals across the United States.

“It was a proud moment for Cision Vision to be part of this event and discuss our recent progress in the field of medical imaging and cancer care,” says Li, who is a co-founder and the CEO of CisionVision. “It was a humbling experience for us to hear directly from patient advocates and cancer survivors at the event. We feel more inspired than ever to bring better solutions for cancer care to patients around the world.”

Other technologies shown at the event included new approaches such as a tortoise-shaped pill designed to enhance the efficacy of oral medicines, a miniature organ-on-a-chip liver device to predict drug toxicity and model liver disease, and a wireless bioelectronic device that provides oxygen for cell therapy applications and for the treatment of chronic disease.

“The feedback from the organizers and the audience at the event has been overwhelmingly positive,” says Tarek Fadel, who led the team’s participation at the event. “Navigating the demonstration space felt like stepping into the future. As a center, we stand poised to engineer transformative tools that will truly make a difference for the future of cancer care.”

Sangeeta Bhatia, the Director of the Marble Center and the John J. and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science, adds: “The showcase of our technologies at the White House Demo Day underscores the transformative impact we aim to achieve in cancer detection and treatment. The event highlights our vision to advance cutting-edge solutions for the benefit of patients and communities worldwide.”

Some Covid-19 vaccines safely and effectively used lipid nanoparticles (LNPs) to deliver messenger RNA to cells. A new MIT study shows that different nanoparticles could be used for a potential Alzheimer’s disease (AD) therapy. In tests in multiple mouse models and with cultured human cells, a newly tailored LNP formulation effectively delivered small interfering RNA (siRNA) to the brain’s microglia immune cells to suppress expression of a protein linked to excessive inflammation in Alzheimer’s disease.

In a prior study, the researchers showed that blocking the consequences of PU.1 protein activity helps to reduce Alzheimer’s disease-related neuroinflammation and pathology. The new open-access results, reported in the journal Advanced Materials, achieves a reduction in inflammation by directly tamping down expression of the Spi1 gene that encodes PU.1. More generally, the new study also demonstrates a new way to deliver RNA to microglia, which have been difficult to target so far.

Study co-senior author Li-Huei Tsai, the Picower professor of neuroscience and director of The Picower Institute for Learning and Memory and Aging Brain Initiative at MIT, says she hypothesized that LNPs might work as a way to bring siRNA into microglia because the cells, which clear waste in the brain, have a strong proclivity to uptake lipid molecules. She discussed this with Robert Langer, the David Koch Institute Professor, who is widely known for his influential work on nanoparticle drug delivery. They decided to test the idea of reducing PU.1 expression with an LNP-delivered siRNA.

“I still remember the day when I asked to meet with Bob to discuss the idea of testing LNPs as a payload to target inflammatory microglia,” says Tsai, a faculty member in the Department of Brain and Cognitive Sciences. “I am very grateful to The JPB Foundation, who supported this idea without any preliminary evidence.”

Langer Lab graduate student Jason Andresen and former Tsai Lab postdoc William Ralvenius led the work and are the study’s co-lead authors. Owen Fenton, a former Langer Lab postdoc who is now an assistant professor at the University of North Carolina’s Eshelman School of Pharmacy, is a co-corresponding author along with Tsai and Langer. Langer is a professor in the departments of Chemical Engineering and Biological Engineering, and the Koch Institute for Integrative Cancer Research.

Perfecting a particle

The simplest way to test whether siRNA could therapeutically suppress PU.1 expression would have been to make use of an already available delivery device, but one of the first discoveries in the study is that none of eight commercially available reagents could safely and effectively transfect cultured human microglia-like cells in the lab.

Instead, the team had to optimize an LNP to do the job. LNPs have four main components; by changing the structures of two of them, and by varying the ratio of lipids to RNA, the researchers were able to come up with seven formulations to try. Importantly, their testing included trying their formulations on cultured microglia that they had induced into an inflammatory state. That state, after all, is the one in which the proposed treatment is needed.

Among the seven candidates, one the team named “MG-LNP” stood out for its especially high delivery efficiency and safety of a test RNA cargo.

What works in a dish sometimes doesn’t work in a living organism, so the team next tested their LNP formulations’ effectiveness and safety in mice. Testing two different methods of injection, into the body or into the cerebrospinal fluid (CSF), they found that injection into the CSF ensured much greater efficacy in targeting microglia without affecting cells in other organs. Among the seven formulations, MG-LNP again proved the most effective at transfecting microglia. Langer said he believes this could potentially open new ways of treating certain brain diseases with nanoparticles someday. 

A targeted therapy

Once they knew MG-LNP could deliver a test cargo to microglia both in human cell cultures and mice, the scientists then tested whether using it to deliver a PU.1-suppressing siRNA could reduce inflammation in microglia. In the cell cultures, a relatively low dose achieved a 42 percent reduction of PU.1 expression (which is good because microglia need at least some PU.1 to live). Indeed, MG-LNP transfection did not cause the cells any harm. It also significantly reduced the transcription of the genes that PU.1 expression increases in microglia, indicating that it can reduce multiple inflammatory markers.

In all these measures, and others, MG-LNP outperformed a commercially available reagent called RNAiMAX that the scientists tested in parallel.

“These findings support the use of MG-LNP-mediated anti-PU.1 siRNA delivery as a potential therapy for neuroinflammatory diseases,” the researchers wrote.

The final set of tests evaluated MG-LNP’s performance delivering the siRNA in two mouse models of inflammation in the brain. In one, mice were exposed to LPS, a molecule that simulates infection and stimulates a systemic inflammation response. In the other model, mice exhibit severe neurodegeneration and inflammation when an enzyme called CDK5 becomes hyperactivated by a protein called p25.

In both models, injection of MG-LNPs carrying the anti-PU.1 siRNA reduced expression of PU.1 and inflammatory markers, much like in the cultured human cells.

“MG-LNP delivery of anti-PU.1 siRNA can potentially be used as an anti-inflammatory therapeutic in mice with systemic inflammation an in the CK-p25 mouse model of AD-like neuroinflammation,” the scientists concluded, calling the results a “proof-of-principle.” More testing will be required before the idea could be tried in human patients.

In addition to Andresen, Ralvenius, Langer, Tsai, and Owen, the paper’s other authors are Margaret Huston, Jay Penney, and Julia Maeve Bonner.

In addition to the The JPB Foundation and The Picower Institute for Learning and Memory, the Robert and Renee Belfer Family, Eduardo Eurnekian, Lester A. Gimpelson, Jay L. and Carroll Miller, the Koch Institute, the Swiss National Science Foundation, and the Alzheimer’s Association provided funding for the study.

Many of the most promising new pharmaceuticals coming along in the drug development pathway are hydrophobic by nature — that is, they repel water, and are thus hard to dissolve in order to make them available to the body. But now, researchers at MIT have found a more efficient way of processing and delivering these drugs that could make them far more effective.

The new method, which involves initially processing the drugs in a liquid solution rather than in solid form, is reported in a paper in the Dec. 15 print issue of the journal Advanced Healthcare Materials, written by MIT graduate student Lucas Attia, recent graduate Liang-Hsun Chen PhD ’22, and professor of chemical engineering Patrick Doyle.

Currently, much drug processing is done through a long series of sequential steps, Doyle explains. “We think we can streamline the process, but also get better products, by combining these steps and leveraging our understanding of soft matter and self-assembly processes,” he says.

Attia adds that “a lot of small-molecule active ingredients are hydrophobic, so they don’t like being in water and they have very poor dissolution in water, which leads to their poor bioavailability.” Giving such drugs orally, which patients prefer over injections, presents real challenges in getting the material into the patient’s bloodstream. Up to 90 percent of the candidate drug molecules being developed by pharmaceutical companies actually are hydrophobic, he says, “so this is relevant to a large class of potential drug molecules.”

Another advantage of the new process, he says, is that it should make it easier to combine multiple different drugs in a single pill. “For different types of diseases where you’re taking multiple drugs at the same time, this kind of product can be very important in improving patient compliance,” he adds — only having to take one pill instead of a handful makes it much more likely that patients will keep up with their medications. “That’s actually a big issue with these chronic illnesses where patients are on very challenging pill regimes, so combination products have been shown to help a lot.”

One key to the new process is the use of a hydrogel — a sort of sponge-like gel material that can retain water and hold molecules in place. Present processes for making hydrophobic materials more bioavailable involve mechanically grinding the crystals down to smaller size, which makes them dissolve more readily, but this process adds time and expense to the manufacturing process, provides little control over the size distribution of the particles, and can actually damage some more delicate drug molecules.

Instead, the new process involves dissolving the drug in a carrier solution, then generating tiny nanodroplets of this carrier dispersed throughout a polymer solution — a material called a nanoemulsion. Then, this nanoemulsion is squeezed through a syringe and gelled into a hydrogel. The hydrogel holds the droplets in place as the carrier evaporates, leaving behind drug nanocrystals. This approach allows precise control over the final crystal size. The hydrogel, by keeping the droplets in place as they dry, prevents them from simply merging together to form lumpy agglomerations of different sizes. Without the hydrogel the droplets would merge randomly, and “you’d get a mess,” Doyle says. Instead, the new process leaves a batch of perfectly uniform nanoparticles. “That’s a very unique, novel way that our group has invented, to do this sort of crystallization and maintain the nano size,” he says.

The new process yields a two-part package: a core, which contains the active molecules, surrounded by a shell, also made of hydrogel, which can control the timing between ingestion of the pill and the release of its contents into the body.

“We showed that we can get very precise control over the drug release, both in terms of delay and rate,” says Doyle, who is the Robert T. Haslam Professor of Chemical Engineering and Singapore Research Professor. For example, if a drug is targeting disease in the lower intestine or colon, “we can control how long until the drug release starts, and then we also get very fast release once it begins.” Drugs formulated the conventional way with mechanical nanomilling, he says, “would have a slow drug release.”

This process, Attia says, “is the first approach that can form core-shell composite particles and structure drugs in distinct polymeric layers in a single processing step.”

The next steps in developing the process will be to test the system on a wide variety of drug molecules, beyond the two representative examples that were tested so far, Doyle says. Although they have reason to believe the process is generalizable, he says, “the proof is in the pudding — having the data in hand.”

The dripping process they use, he says, “can be scalable, but there’s a lot of details to be worked out.” But because all of the materials they are working with have been chosen as ones that are already recognized as safe for medical use, the approval process should be straightforward, he says. “It could be implemented in a few years. … We’re not worrying about all those typical safety hurdles that I think other novel formulations have to go through, which can be very expensive.”

The work received support from the U.S. Department of Energy.

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.

On Nov. 7, a team from the Marble Center for Cancer Nanomedicine at MIT showed a Washington audience several examples of how nanotechnologies developed at the Institute can transform the detection and treatment of cancer and other diseases.

The team was one of 40 innovative groups featured at “American Possibilities: A White House Demo Day.” Technology on view spanned energy, artificial intelligence, climate, and health, highlighting advancements that contribute to building a better future for all Americans.

Participants included President Joe Biden, Biden-Harris administration leaders and White House staff, members of Congress, federal R&D funding agencies, scientists and engineers, academics, students, and science and technology industry innovators. The event holds special significance for MIT as eight years ago, MIT's Computer Science and Artificial Intelligence Laboratory participated in the last iteration of the White House Demo Day under President Barack Obama.

“It was truly inspirational hearing from experts from all across the government, the private sector, and academia touching on so many fields,” said President Biden of the event. “It was a reminder, at least for me, of what I’ve long believed — that America can be defined by a single word... possibilities.”

Launched in 2016, the Marble Center for Cancer Nanomedicine was established at the Koch Institute for Integrative Research at MIT to serve as a hub for miniaturized biomedical technologies, especially those that address grand challenges in cancer detection, treatment, and monitoring. The center convenes Koch Institute faculty members Sangeeta Bhatia, Paula Hammond, Robert Langer, Angela Belcher, Darrell Irvine, and Daniel Anderson to advance nanomedicine, as well as to facilitate collaboration with industry partners, including Alloy Therapeutics, Danaher Corp., Fujifilm, and Sanofi. 

Ana Jaklenec, a principal research scientist at the Koch Institute, highlighted several groundbreaking technologies in vaccines and disease diagnostics and treatment at the event. Jaklenec gave demonstrations from projects from her research group, including novel vaccine formulations capable of releasing a dozen booster doses pulsed over predetermined time points, microneedle vaccine technologies, and nutrient delivery technologies for precise control over microbiome modulation and nutrient absorption.

Jaklenec describes the event as “a wonderful opportunity to meet our government leaders and policymakers and see their passion for curing cancer. But it was especially moving to interact with people representing diverse communities across the United States and hear their excitement for how our technologies could positively impact their communities.”

Jeremy Li, a former MIT postdoc, presented a technology developed in the Belcher laboratory and commercialized by the spinout Cision Vision. The startup is developing a new approach to visualize lymph nodes in real time without any injection or radiation. The shoebox-sized device was also selected as part of Time Magazine’s Best Inventions of 2023 and is currently being used in a dozen hospitals across the United States.

“It was a proud moment for Cision Vision to be part of this event and discuss our recent progress in the field of medical imaging and cancer care,” says Li, who is a co-founder and the CEO of CisionVision. “It was a humbling experience for us to hear directly from patient advocates and cancer survivors at the event. We feel more inspired than ever to bring better solutions for cancer care to patients around the world.”

Other technologies shown at the event included new approaches such as a tortoise-shaped pill designed to enhance the efficacy of oral medicines, a miniature organ-on-a-chip liver device to predict drug toxicity and model liver disease, and a wireless bioelectronic device that provides oxygen for cell therapy applications and for the treatment of chronic disease.

“The feedback from the organizers and the audience at the event has been overwhelmingly positive,” says Tarek Fadel, who led the team’s participation at the event. “Navigating the demonstration space felt like stepping into the future. As a center, we stand poised to engineer transformative tools that will truly make a difference for the future of cancer care.”

Sangeeta Bhatia, the Director of the Marble Center and the John J. and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science, adds: “The showcase of our technologies at the White House Demo Day underscores the transformative impact we aim to achieve in cancer detection and treatment. The event highlights our vision to advance cutting-edge solutions for the benefit of patients and communities worldwide.”

Some Covid-19 vaccines safely and effectively used lipid nanoparticles (LNPs) to deliver messenger RNA to cells. A new MIT study shows that different nanoparticles could be used for a potential Alzheimer’s disease (AD) therapy. In tests in multiple mouse models and with cultured human cells, a newly tailored LNP formulation effectively delivered small interfering RNA (siRNA) to the brain’s microglia immune cells to suppress expression of a protein linked to excessive inflammation in Alzheimer’s disease.

In a prior study, the researchers showed that blocking the consequences of PU.1 protein activity helps to reduce Alzheimer’s disease-related neuroinflammation and pathology. The new open-access results, reported in the journal Advanced Materials, achieves a reduction in inflammation by directly tamping down expression of the Spi1 gene that encodes PU.1. More generally, the new study also demonstrates a new way to deliver RNA to microglia, which have been difficult to target so far.

Study co-senior author Li-Huei Tsai, the Picower professor of neuroscience and director of The Picower Institute for Learning and Memory and Aging Brain Initiative at MIT, says she hypothesized that LNPs might work as a way to bring siRNA into microglia because the cells, which clear waste in the brain, have a strong proclivity to uptake lipid molecules. She discussed this with Robert Langer, the David Koch Institute Professor, who is widely known for his influential work on nanoparticle drug delivery. They decided to test the idea of reducing PU.1 expression with an LNP-delivered siRNA.

“I still remember the day when I asked to meet with Bob to discuss the idea of testing LNPs as a payload to target inflammatory microglia,” says Tsai, a faculty member in the Department of Brain and Cognitive Sciences. “I am very grateful to The JPB Foundation, who supported this idea without any preliminary evidence.”

Langer Lab graduate student Jason Andresen and former Tsai Lab postdoc William Ralvenius led the work and are the study’s co-lead authors. Owen Fenton, a former Langer Lab postdoc who is now an assistant professor at the University of North Carolina’s Eshelman School of Pharmacy, is a co-corresponding author along with Tsai and Langer. Langer is a professor in the departments of Chemical Engineering and Biological Engineering, and the Koch Institute for Integrative Cancer Research.

Perfecting a particle

The simplest way to test whether siRNA could therapeutically suppress PU.1 expression would have been to make use of an already available delivery device, but one of the first discoveries in the study is that none of eight commercially available reagents could safely and effectively transfect cultured human microglia-like cells in the lab.

Instead, the team had to optimize an LNP to do the job. LNPs have four main components; by changing the structures of two of them, and by varying the ratio of lipids to RNA, the researchers were able to come up with seven formulations to try. Importantly, their testing included trying their formulations on cultured microglia that they had induced into an inflammatory state. That state, after all, is the one in which the proposed treatment is needed.

Among the seven candidates, one the team named “MG-LNP” stood out for its especially high delivery efficiency and safety of a test RNA cargo.

What works in a dish sometimes doesn’t work in a living organism, so the team next tested their LNP formulations’ effectiveness and safety in mice. Testing two different methods of injection, into the body or into the cerebrospinal fluid (CSF), they found that injection into the CSF ensured much greater efficacy in targeting microglia without affecting cells in other organs. Among the seven formulations, MG-LNP again proved the most effective at transfecting microglia. Langer said he believes this could potentially open new ways of treating certain brain diseases with nanoparticles someday. 

A targeted therapy

Once they knew MG-LNP could deliver a test cargo to microglia both in human cell cultures and mice, the scientists then tested whether using it to deliver a PU.1-suppressing siRNA could reduce inflammation in microglia. In the cell cultures, a relatively low dose achieved a 42 percent reduction of PU.1 expression (which is good because microglia need at least some PU.1 to live). Indeed, MG-LNP transfection did not cause the cells any harm. It also significantly reduced the transcription of the genes that PU.1 expression increases in microglia, indicating that it can reduce multiple inflammatory markers.

In all these measures, and others, MG-LNP outperformed a commercially available reagent called RNAiMAX that the scientists tested in parallel.

“These findings support the use of MG-LNP-mediated anti-PU.1 siRNA delivery as a potential therapy for neuroinflammatory diseases,” the researchers wrote.

The final set of tests evaluated MG-LNP’s performance delivering the siRNA in two mouse models of inflammation in the brain. In one, mice were exposed to LPS, a molecule that simulates infection and stimulates a systemic inflammation response. In the other model, mice exhibit severe neurodegeneration and inflammation when an enzyme called CDK5 becomes hyperactivated by a protein called p25.

In both models, injection of MG-LNPs carrying the anti-PU.1 siRNA reduced expression of PU.1 and inflammatory markers, much like in the cultured human cells.

“MG-LNP delivery of anti-PU.1 siRNA can potentially be used as an anti-inflammatory therapeutic in mice with systemic inflammation an in the CK-p25 mouse model of AD-like neuroinflammation,” the scientists concluded, calling the results a “proof-of-principle.” More testing will be required before the idea could be tried in human patients.

In addition to Andresen, Ralvenius, Langer, Tsai, and Owen, the paper’s other authors are Margaret Huston, Jay Penney, and Julia Maeve Bonner.

In addition to the The JPB Foundation and The Picower Institute for Learning and Memory, the Robert and Renee Belfer Family, Eduardo Eurnekian, Lester A. Gimpelson, Jay L. and Carroll Miller, the Koch Institute, the Swiss National Science Foundation, and the Alzheimer’s Association provided funding for the study.

Many of the most promising new pharmaceuticals coming along in the drug development pathway are hydrophobic by nature — that is, they repel water, and are thus hard to dissolve in order to make them available to the body. But now, researchers at MIT have found a more efficient way of processing and delivering these drugs that could make them far more effective.

The new method, which involves initially processing the drugs in a liquid solution rather than in solid form, is reported in a paper in the Dec. 15 print issue of the journal Advanced Healthcare Materials, written by MIT graduate student Lucas Attia, recent graduate Liang-Hsun Chen PhD ’22, and professor of chemical engineering Patrick Doyle.

Currently, much drug processing is done through a long series of sequential steps, Doyle explains. “We think we can streamline the process, but also get better products, by combining these steps and leveraging our understanding of soft matter and self-assembly processes,” he says.

Attia adds that “a lot of small-molecule active ingredients are hydrophobic, so they don’t like being in water and they have very poor dissolution in water, which leads to their poor bioavailability.” Giving such drugs orally, which patients prefer over injections, presents real challenges in getting the material into the patient’s bloodstream. Up to 90 percent of the candidate drug molecules being developed by pharmaceutical companies actually are hydrophobic, he says, “so this is relevant to a large class of potential drug molecules.”

Another advantage of the new process, he says, is that it should make it easier to combine multiple different drugs in a single pill. “For different types of diseases where you’re taking multiple drugs at the same time, this kind of product can be very important in improving patient compliance,” he adds — only having to take one pill instead of a handful makes it much more likely that patients will keep up with their medications. “That’s actually a big issue with these chronic illnesses where patients are on very challenging pill regimes, so combination products have been shown to help a lot.”

One key to the new process is the use of a hydrogel — a sort of sponge-like gel material that can retain water and hold molecules in place. Present processes for making hydrophobic materials more bioavailable involve mechanically grinding the crystals down to smaller size, which makes them dissolve more readily, but this process adds time and expense to the manufacturing process, provides little control over the size distribution of the particles, and can actually damage some more delicate drug molecules.

Instead, the new process involves dissolving the drug in a carrier solution, then generating tiny nanodroplets of this carrier dispersed throughout a polymer solution — a material called a nanoemulsion. Then, this nanoemulsion is squeezed through a syringe and gelled into a hydrogel. The hydrogel holds the droplets in place as the carrier evaporates, leaving behind drug nanocrystals. This approach allows precise control over the final crystal size. The hydrogel, by keeping the droplets in place as they dry, prevents them from simply merging together to form lumpy agglomerations of different sizes. Without the hydrogel the droplets would merge randomly, and “you’d get a mess,” Doyle says. Instead, the new process leaves a batch of perfectly uniform nanoparticles. “That’s a very unique, novel way that our group has invented, to do this sort of crystallization and maintain the nano size,” he says.

The new process yields a two-part package: a core, which contains the active molecules, surrounded by a shell, also made of hydrogel, which can control the timing between ingestion of the pill and the release of its contents into the body.

“We showed that we can get very precise control over the drug release, both in terms of delay and rate,” says Doyle, who is the Robert T. Haslam Professor of Chemical Engineering and Singapore Research Professor. For example, if a drug is targeting disease in the lower intestine or colon, “we can control how long until the drug release starts, and then we also get very fast release once it begins.” Drugs formulated the conventional way with mechanical nanomilling, he says, “would have a slow drug release.”

This process, Attia says, “is the first approach that can form core-shell composite particles and structure drugs in distinct polymeric layers in a single processing step.”

The next steps in developing the process will be to test the system on a wide variety of drug molecules, beyond the two representative examples that were tested so far, Doyle says. Although they have reason to believe the process is generalizable, he says, “the proof is in the pudding — having the data in hand.”

The dripping process they use, he says, “can be scalable, but there’s a lot of details to be worked out.” But because all of the materials they are working with have been chosen as ones that are already recognized as safe for medical use, the approval process should be straightforward, he says. “It could be implemented in a few years. … We’re not worrying about all those typical safety hurdles that I think other novel formulations have to go through, which can be very expensive.”

The work received support from the U.S. Department of Energy.

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.

On Nov. 7, a team from the Marble Center for Cancer Nanomedicine at MIT showed a Washington audience several examples of how nanotechnologies developed at the Institute can transform the detection and treatment of cancer and other diseases.

The team was one of 40 innovative groups featured at “American Possibilities: A White House Demo Day.” Technology on view spanned energy, artificial intelligence, climate, and health, highlighting advancements that contribute to building a better future for all Americans.

Participants included President Joe Biden, Biden-Harris administration leaders and White House staff, members of Congress, federal R&D funding agencies, scientists and engineers, academics, students, and science and technology industry innovators. The event holds special significance for MIT as eight years ago, MIT's Computer Science and Artificial Intelligence Laboratory participated in the last iteration of the White House Demo Day under President Barack Obama.

“It was truly inspirational hearing from experts from all across the government, the private sector, and academia touching on so many fields,” said President Biden of the event. “It was a reminder, at least for me, of what I’ve long believed — that America can be defined by a single word... possibilities.”

Launched in 2016, the Marble Center for Cancer Nanomedicine was established at the Koch Institute for Integrative Research at MIT to serve as a hub for miniaturized biomedical technologies, especially those that address grand challenges in cancer detection, treatment, and monitoring. The center convenes Koch Institute faculty members Sangeeta Bhatia, Paula Hammond, Robert Langer, Angela Belcher, Darrell Irvine, and Daniel Anderson to advance nanomedicine, as well as to facilitate collaboration with industry partners, including Alloy Therapeutics, Danaher Corp., Fujifilm, and Sanofi. 

Ana Jaklenec, a principal research scientist at the Koch Institute, highlighted several groundbreaking technologies in vaccines and disease diagnostics and treatment at the event. Jaklenec gave demonstrations from projects from her research group, including novel vaccine formulations capable of releasing a dozen booster doses pulsed over predetermined time points, microneedle vaccine technologies, and nutrient delivery technologies for precise control over microbiome modulation and nutrient absorption.

Jaklenec describes the event as “a wonderful opportunity to meet our government leaders and policymakers and see their passion for curing cancer. But it was especially moving to interact with people representing diverse communities across the United States and hear their excitement for how our technologies could positively impact their communities.”

Jeremy Li, a former MIT postdoc, presented a technology developed in the Belcher laboratory and commercialized by the spinout Cision Vision. The startup is developing a new approach to visualize lymph nodes in real time without any injection or radiation. The shoebox-sized device was also selected as part of Time Magazine’s Best Inventions of 2023 and is currently being used in a dozen hospitals across the United States.

“It was a proud moment for Cision Vision to be part of this event and discuss our recent progress in the field of medical imaging and cancer care,” says Li, who is a co-founder and the CEO of CisionVision. “It was a humbling experience for us to hear directly from patient advocates and cancer survivors at the event. We feel more inspired than ever to bring better solutions for cancer care to patients around the world.”

Other technologies shown at the event included new approaches such as a tortoise-shaped pill designed to enhance the efficacy of oral medicines, a miniature organ-on-a-chip liver device to predict drug toxicity and model liver disease, and a wireless bioelectronic device that provides oxygen for cell therapy applications and for the treatment of chronic disease.

“The feedback from the organizers and the audience at the event has been overwhelmingly positive,” says Tarek Fadel, who led the team’s participation at the event. “Navigating the demonstration space felt like stepping into the future. As a center, we stand poised to engineer transformative tools that will truly make a difference for the future of cancer care.”

Sangeeta Bhatia, the Director of the Marble Center and the John J. and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science, adds: “The showcase of our technologies at the White House Demo Day underscores the transformative impact we aim to achieve in cancer detection and treatment. The event highlights our vision to advance cutting-edge solutions for the benefit of patients and communities worldwide.”

Some Covid-19 vaccines safely and effectively used lipid nanoparticles (LNPs) to deliver messenger RNA to cells. A new MIT study shows that different nanoparticles could be used for a potential Alzheimer’s disease (AD) therapy. In tests in multiple mouse models and with cultured human cells, a newly tailored LNP formulation effectively delivered small interfering RNA (siRNA) to the brain’s microglia immune cells to suppress expression of a protein linked to excessive inflammation in Alzheimer’s disease.

In a prior study, the researchers showed that blocking the consequences of PU.1 protein activity helps to reduce Alzheimer’s disease-related neuroinflammation and pathology. The new open-access results, reported in the journal Advanced Materials, achieves a reduction in inflammation by directly tamping down expression of the Spi1 gene that encodes PU.1. More generally, the new study also demonstrates a new way to deliver RNA to microglia, which have been difficult to target so far.

Study co-senior author Li-Huei Tsai, the Picower professor of neuroscience and director of The Picower Institute for Learning and Memory and Aging Brain Initiative at MIT, says she hypothesized that LNPs might work as a way to bring siRNA into microglia because the cells, which clear waste in the brain, have a strong proclivity to uptake lipid molecules. She discussed this with Robert Langer, the David Koch Institute Professor, who is widely known for his influential work on nanoparticle drug delivery. They decided to test the idea of reducing PU.1 expression with an LNP-delivered siRNA.

“I still remember the day when I asked to meet with Bob to discuss the idea of testing LNPs as a payload to target inflammatory microglia,” says Tsai, a faculty member in the Department of Brain and Cognitive Sciences. “I am very grateful to The JPB Foundation, who supported this idea without any preliminary evidence.”

Langer Lab graduate student Jason Andresen and former Tsai Lab postdoc William Ralvenius led the work and are the study’s co-lead authors. Owen Fenton, a former Langer Lab postdoc who is now an assistant professor at the University of North Carolina’s Eshelman School of Pharmacy, is a co-corresponding author along with Tsai and Langer. Langer is a professor in the departments of Chemical Engineering and Biological Engineering, and the Koch Institute for Integrative Cancer Research.

Perfecting a particle

The simplest way to test whether siRNA could therapeutically suppress PU.1 expression would have been to make use of an already available delivery device, but one of the first discoveries in the study is that none of eight commercially available reagents could safely and effectively transfect cultured human microglia-like cells in the lab.

Instead, the team had to optimize an LNP to do the job. LNPs have four main components; by changing the structures of two of them, and by varying the ratio of lipids to RNA, the researchers were able to come up with seven formulations to try. Importantly, their testing included trying their formulations on cultured microglia that they had induced into an inflammatory state. That state, after all, is the one in which the proposed treatment is needed.

Among the seven candidates, one the team named “MG-LNP” stood out for its especially high delivery efficiency and safety of a test RNA cargo.

What works in a dish sometimes doesn’t work in a living organism, so the team next tested their LNP formulations’ effectiveness and safety in mice. Testing two different methods of injection, into the body or into the cerebrospinal fluid (CSF), they found that injection into the CSF ensured much greater efficacy in targeting microglia without affecting cells in other organs. Among the seven formulations, MG-LNP again proved the most effective at transfecting microglia. Langer said he believes this could potentially open new ways of treating certain brain diseases with nanoparticles someday. 

A targeted therapy

Once they knew MG-LNP could deliver a test cargo to microglia both in human cell cultures and mice, the scientists then tested whether using it to deliver a PU.1-suppressing siRNA could reduce inflammation in microglia. In the cell cultures, a relatively low dose achieved a 42 percent reduction of PU.1 expression (which is good because microglia need at least some PU.1 to live). Indeed, MG-LNP transfection did not cause the cells any harm. It also significantly reduced the transcription of the genes that PU.1 expression increases in microglia, indicating that it can reduce multiple inflammatory markers.

In all these measures, and others, MG-LNP outperformed a commercially available reagent called RNAiMAX that the scientists tested in parallel.

“These findings support the use of MG-LNP-mediated anti-PU.1 siRNA delivery as a potential therapy for neuroinflammatory diseases,” the researchers wrote.

The final set of tests evaluated MG-LNP’s performance delivering the siRNA in two mouse models of inflammation in the brain. In one, mice were exposed to LPS, a molecule that simulates infection and stimulates a systemic inflammation response. In the other model, mice exhibit severe neurodegeneration and inflammation when an enzyme called CDK5 becomes hyperactivated by a protein called p25.

In both models, injection of MG-LNPs carrying the anti-PU.1 siRNA reduced expression of PU.1 and inflammatory markers, much like in the cultured human cells.

“MG-LNP delivery of anti-PU.1 siRNA can potentially be used as an anti-inflammatory therapeutic in mice with systemic inflammation an in the CK-p25 mouse model of AD-like neuroinflammation,” the scientists concluded, calling the results a “proof-of-principle.” More testing will be required before the idea could be tried in human patients.

In addition to Andresen, Ralvenius, Langer, Tsai, and Owen, the paper’s other authors are Margaret Huston, Jay Penney, and Julia Maeve Bonner.

In addition to the The JPB Foundation and The Picower Institute for Learning and Memory, the Robert and Renee Belfer Family, Eduardo Eurnekian, Lester A. Gimpelson, Jay L. and Carroll Miller, the Koch Institute, the Swiss National Science Foundation, and the Alzheimer’s Association provided funding for the study.

Many of the most promising new pharmaceuticals coming along in the drug development pathway are hydrophobic by nature — that is, they repel water, and are thus hard to dissolve in order to make them available to the body. But now, researchers at MIT have found a more efficient way of processing and delivering these drugs that could make them far more effective.

The new method, which involves initially processing the drugs in a liquid solution rather than in solid form, is reported in a paper in the Dec. 15 print issue of the journal Advanced Healthcare Materials, written by MIT graduate student Lucas Attia, recent graduate Liang-Hsun Chen PhD ’22, and professor of chemical engineering Patrick Doyle.

Currently, much drug processing is done through a long series of sequential steps, Doyle explains. “We think we can streamline the process, but also get better products, by combining these steps and leveraging our understanding of soft matter and self-assembly processes,” he says.

Attia adds that “a lot of small-molecule active ingredients are hydrophobic, so they don’t like being in water and they have very poor dissolution in water, which leads to their poor bioavailability.” Giving such drugs orally, which patients prefer over injections, presents real challenges in getting the material into the patient’s bloodstream. Up to 90 percent of the candidate drug molecules being developed by pharmaceutical companies actually are hydrophobic, he says, “so this is relevant to a large class of potential drug molecules.”

Another advantage of the new process, he says, is that it should make it easier to combine multiple different drugs in a single pill. “For different types of diseases where you’re taking multiple drugs at the same time, this kind of product can be very important in improving patient compliance,” he adds — only having to take one pill instead of a handful makes it much more likely that patients will keep up with their medications. “That’s actually a big issue with these chronic illnesses where patients are on very challenging pill regimes, so combination products have been shown to help a lot.”

One key to the new process is the use of a hydrogel — a sort of sponge-like gel material that can retain water and hold molecules in place. Present processes for making hydrophobic materials more bioavailable involve mechanically grinding the crystals down to smaller size, which makes them dissolve more readily, but this process adds time and expense to the manufacturing process, provides little control over the size distribution of the particles, and can actually damage some more delicate drug molecules.

Instead, the new process involves dissolving the drug in a carrier solution, then generating tiny nanodroplets of this carrier dispersed throughout a polymer solution — a material called a nanoemulsion. Then, this nanoemulsion is squeezed through a syringe and gelled into a hydrogel. The hydrogel holds the droplets in place as the carrier evaporates, leaving behind drug nanocrystals. This approach allows precise control over the final crystal size. The hydrogel, by keeping the droplets in place as they dry, prevents them from simply merging together to form lumpy agglomerations of different sizes. Without the hydrogel the droplets would merge randomly, and “you’d get a mess,” Doyle says. Instead, the new process leaves a batch of perfectly uniform nanoparticles. “That’s a very unique, novel way that our group has invented, to do this sort of crystallization and maintain the nano size,” he says.

The new process yields a two-part package: a core, which contains the active molecules, surrounded by a shell, also made of hydrogel, which can control the timing between ingestion of the pill and the release of its contents into the body.

“We showed that we can get very precise control over the drug release, both in terms of delay and rate,” says Doyle, who is the Robert T. Haslam Professor of Chemical Engineering and Singapore Research Professor. For example, if a drug is targeting disease in the lower intestine or colon, “we can control how long until the drug release starts, and then we also get very fast release once it begins.” Drugs formulated the conventional way with mechanical nanomilling, he says, “would have a slow drug release.”

This process, Attia says, “is the first approach that can form core-shell composite particles and structure drugs in distinct polymeric layers in a single processing step.”

The next steps in developing the process will be to test the system on a wide variety of drug molecules, beyond the two representative examples that were tested so far, Doyle says. Although they have reason to believe the process is generalizable, he says, “the proof is in the pudding — having the data in hand.”

The dripping process they use, he says, “can be scalable, but there’s a lot of details to be worked out.” But because all of the materials they are working with have been chosen as ones that are already recognized as safe for medical use, the approval process should be straightforward, he says. “It could be implemented in a few years. … We’re not worrying about all those typical safety hurdles that I think other novel formulations have to go through, which can be very expensive.”

The work received support from the U.S. Department of Energy.