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.

Enlarge / The spliceosome is a large complex of proteins and RNAs. (credit: NCBI)

Almost 1,500 genes have been implicated in intellectual disabilities; yet for most people with such disabilities, genetic causes remain unknown. Perhaps this is in part because geneticists have been focusing on the wrong stretches of DNA when they go searching. To rectify this, Ernest Turro—a biostatistician who focuses on genetics, genomics, and molecular diagnostics—used whole genome sequencing data from the 100,000 Genomes Project to search for areas associated with intellectual disabilities.

His lab found a genetic association that is the most common one yet to be associated with neurodevelopmental abnormality. And the gene they identified doesn’t even make a protein.

Trouble with the spliceosome

Most genes include instructions for how to make proteins. That’s true. And yet human genes are not arranged linearly—or rather, they are arranged linearly, but not contiguously. A gene containing the instructions for which amino acids to string together to make a particular protein—hemoglobin, insulin, serotonin, albumin, estrogen, whatever protein you like—is modular. It contains part of the amino acid sequence, then it has a chunk of DNA that is largely irrelevant to that sequence, then a bit more of the protein’s sequence, then another chunk of random DNA, back and forth until the end of the protein. It’s as if each of these prose paragraphs were separated by a string of unrelated letters (but not a meaningful paragraph from a different article).

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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.

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.

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.

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.

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.

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.

RNA vaccines against Covid-19 have proven effective at reducing the severity of disease. However, a team of researchers at MIT is working on making them even better. By tweaking the design of the vaccines, the researchers showed that they could generate Covid-19 RNA vaccines that produce a stronger immune response, at a lower dose, in mice.

Adjuvants are molecules commonly used to increase the immune response to vaccines, but they haven’t yet been used in RNA vaccines.  In this study, the MIT researchers engineered both the nanoparticles used to deliver the Covid-19 antigen, and the antigen itself, to boost the immune response, without the need for a separate adjuvant.

If further developed for use in humans, this type of RNA vaccine could help to reduce costs, reduce the dosage needed, and potentially lead to longer-lasting immunity. The researchers’ tests also showed that when delivered intranasally, the vaccine induced a strong immune response when compared to the response elicited by traditional, intramuscular vaccination.

“With intranasal vaccination, you might be able to kill Covid at the mucus membrane, before it gets into your body,” says Daniel Anderson, a professor in MIT’s Department of Chemical Engineering, a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science (IMES), and the senior author of the study. “Intranasal vaccines may also be easier to administer to many people, since they don’t require an injection.”

The researchers believe that the effectiveness of other types of RNA vaccines that are now in development, including vaccines for cancer, could be improved by incorporating similar immune-stimulating properties.

Former MIT postdoc Bowen Li, who is now an assistant professor at the University of Toronto; graduate student Allen Jiang; and former MIT postdoc Idris Raji, who was a research fellow at Boston Children’s Hospital, are the lead authors of the new study, which appears today in Nature Biomedical Engineering. The research team also includes Robert Langer, the David H. Koch Institute Professor at MIT and a member of the Koch Institute, and several other MIT researchers.

Boosting immunity

RNA vaccines consist of a strand of RNA that encodes a viral or bacterial protein, also called an antigen. In the case of Covid-19 vaccines, this RNA codes for a segment of the virus’s spike protein. That RNA strand is packaged in a lipid nanoparticle carrier, which protects the RNA from being broken down in the body and helps it get into cells.

Once delivered into cells, the RNA is translated into proteins that the immune system can detect, generating antibodies and T cells that will recognize the protein if the person later becomes infected with the SARS-CoV-2 virus.

The original Covid-19 RNA vaccines developed by Moderna and Pfizer/BioNTech provoked strong immune responses, but the MIT team wanted to see if they could make them more effective by engineering them to have immune stimulatory properties.

In this study, the researchers employed two different strategies to boost the immune response. For the first, they focused on a protein called C3d, which is part of an arm of the immune response known as the complement system. This set of proteins helps the body fight off infection, and C3d’s role is to bind to antigens and amplify the antibody response to those antigens. For many years, scientists have been evaluating the use of C3d as a molecular adjuvant for vaccines made from proteins, such as the DPT vaccine.  

“With the promise of mRNA technologies being realized with the Covid vaccines, we thought that this would be a fantastic opportunity to see if C3d might also be able to play a role as an adjuvant in mRNA vaccine systems,” Jiang says.

To that end, the researchers engineered the mRNA to encode the C3d protein fused to the antigen, so that both components are produced as one protein by cells that receive the vaccine.

In the second phase of their strategy, the researchers modified the lipid nanoparticles used to deliver the RNA vaccine, so that in addition to helping with RNA delivery, the lipids also intrinsically stimulate a stronger immune response.

To identify lipids that would work best, the researchers created a library of 480 lipid nanoparticles with different types of chemistries. All of these are “ionizable” lipids, which become positively charged when they enter acidic environments. The original Covid RNA vaccines also included some ionizable lipids because they help the nanoparticles to self-assemble with RNA and they help target cells to take up the vaccine.

“We understood that nanoparticles themselves could be immunostimulatory, but we weren't quite sure what the chemistry was that was needed to optimize that response. So instead of trying to make the perfect one, we made a library and evaluated them, and through that we identified some chemistries that seemed to improve their response,” Anderson says.

Toward intranasal vaccines

The researchers tested their new vaccine, which included both RNA-encoded C3d and a top-performing ionizable lipid identified from their library screen, in mice. They found that mice injected with this vaccine produced 10 times more antibodies than mice given unadjuvanted Covid RNA vaccines. The new vaccine also provoked a stronger response among T cells, which play important roles in combating the SARS-CoV-2 virus.

“For the first time, we’ve demonstrated a synergistic boost in immune responses by engineering both the RNA and its delivery vehicles,” Li says. “This prompted us to investigate the feasibility of administering this new RNA vaccine platform intranasally, considering the challenges presented by the mucociliary blanket barrier in the upper airways.”

When the researchers delivered the vaccine intranasally, they observed a similarly strong immune response in the mice. If developed for use in people, an intranasal vaccine could potentially offer enhanced protection against infection because it would generate an immune response within the mucosal tissues that line the nasal passages and lungs. 

Because self-adjuvanting vaccines elicit a stronger response at a lower dose, this approach could also help to reduce the cost of vaccine doses, which might allow them to reach more people, especially in developing nations, the researchers say.

Anderson’s lab is now exploring whether this self-adjuvanting platform might also help boost the immune response of other types of RNA vaccines, including cancer vaccines. Working with health care companies, the researchers also plan to test the effectiveness and safety of these new vaccine formulations in larger animal models, in hopes of eventually testing them in patients.

The research was funded by the National Institutes of Health and Translate Bio.

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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.

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.

RNA vaccines against Covid-19 have proven effective at reducing the severity of disease. However, a team of researchers at MIT is working on making them even better. By tweaking the design of the vaccines, the researchers showed that they could generate Covid-19 RNA vaccines that produce a stronger immune response, at a lower dose, in mice.

Adjuvants are molecules commonly used to increase the immune response to vaccines, but they haven’t yet been used in RNA vaccines.  In this study, the MIT researchers engineered both the nanoparticles used to deliver the Covid-19 antigen, and the antigen itself, to boost the immune response, without the need for a separate adjuvant.

If further developed for use in humans, this type of RNA vaccine could help to reduce costs, reduce the dosage needed, and potentially lead to longer-lasting immunity. The researchers’ tests also showed that when delivered intranasally, the vaccine induced a strong immune response when compared to the response elicited by traditional, intramuscular vaccination.

“With intranasal vaccination, you might be able to kill Covid at the mucus membrane, before it gets into your body,” says Daniel Anderson, a professor in MIT’s Department of Chemical Engineering, a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science (IMES), and the senior author of the study. “Intranasal vaccines may also be easier to administer to many people, since they don’t require an injection.”

The researchers believe that the effectiveness of other types of RNA vaccines that are now in development, including vaccines for cancer, could be improved by incorporating similar immune-stimulating properties.

Former MIT postdoc Bowen Li, who is now an assistant professor at the University of Toronto; graduate student Allen Jiang; and former MIT postdoc Idris Raji, who was a research fellow at Boston Children’s Hospital, are the lead authors of the new study, which appears today in Nature Biomedical Engineering. The research team also includes Robert Langer, the David H. Koch Institute Professor at MIT and a member of the Koch Institute, and several other MIT researchers.

Boosting immunity

RNA vaccines consist of a strand of RNA that encodes a viral or bacterial protein, also called an antigen. In the case of Covid-19 vaccines, this RNA codes for a segment of the virus’s spike protein. That RNA strand is packaged in a lipid nanoparticle carrier, which protects the RNA from being broken down in the body and helps it get into cells.

Once delivered into cells, the RNA is translated into proteins that the immune system can detect, generating antibodies and T cells that will recognize the protein if the person later becomes infected with the SARS-CoV-2 virus.

The original Covid-19 RNA vaccines developed by Moderna and Pfizer/BioNTech provoked strong immune responses, but the MIT team wanted to see if they could make them more effective by engineering them to have immune stimulatory properties.

In this study, the researchers employed two different strategies to boost the immune response. For the first, they focused on a protein called C3d, which is part of an arm of the immune response known as the complement system. This set of proteins helps the body fight off infection, and C3d’s role is to bind to antigens and amplify the antibody response to those antigens. For many years, scientists have been evaluating the use of C3d as a molecular adjuvant for vaccines made from proteins, such as the DPT vaccine.  

“With the promise of mRNA technologies being realized with the Covid vaccines, we thought that this would be a fantastic opportunity to see if C3d might also be able to play a role as an adjuvant in mRNA vaccine systems,” Jiang says.

To that end, the researchers engineered the mRNA to encode the C3d protein fused to the antigen, so that both components are produced as one protein by cells that receive the vaccine.

In the second phase of their strategy, the researchers modified the lipid nanoparticles used to deliver the RNA vaccine, so that in addition to helping with RNA delivery, the lipids also intrinsically stimulate a stronger immune response.

To identify lipids that would work best, the researchers created a library of 480 lipid nanoparticles with different types of chemistries. All of these are “ionizable” lipids, which become positively charged when they enter acidic environments. The original Covid RNA vaccines also included some ionizable lipids because they help the nanoparticles to self-assemble with RNA and they help target cells to take up the vaccine.

“We understood that nanoparticles themselves could be immunostimulatory, but we weren't quite sure what the chemistry was that was needed to optimize that response. So instead of trying to make the perfect one, we made a library and evaluated them, and through that we identified some chemistries that seemed to improve their response,” Anderson says.

Toward intranasal vaccines

The researchers tested their new vaccine, which included both RNA-encoded C3d and a top-performing ionizable lipid identified from their library screen, in mice. They found that mice injected with this vaccine produced 10 times more antibodies than mice given unadjuvanted Covid RNA vaccines. The new vaccine also provoked a stronger response among T cells, which play important roles in combating the SARS-CoV-2 virus.

“For the first time, we’ve demonstrated a synergistic boost in immune responses by engineering both the RNA and its delivery vehicles,” Li says. “This prompted us to investigate the feasibility of administering this new RNA vaccine platform intranasally, considering the challenges presented by the mucociliary blanket barrier in the upper airways.”

When the researchers delivered the vaccine intranasally, they observed a similarly strong immune response in the mice. If developed for use in people, an intranasal vaccine could potentially offer enhanced protection against infection because it would generate an immune response within the mucosal tissues that line the nasal passages and lungs. 

Because self-adjuvanting vaccines elicit a stronger response at a lower dose, this approach could also help to reduce the cost of vaccine doses, which might allow them to reach more people, especially in developing nations, the researchers say.

Anderson’s lab is now exploring whether this self-adjuvanting platform might also help boost the immune response of other types of RNA vaccines, including cancer vaccines. Working with health care companies, the researchers also plan to test the effectiveness and safety of these new vaccine formulations in larger animal models, in hopes of eventually testing them in patients.

The research was funded by the National Institutes of Health and Translate Bio.

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.

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.

RNA vaccines against Covid-19 have proven effective at reducing the severity of disease. However, a team of researchers at MIT is working on making them even better. By tweaking the design of the vaccines, the researchers showed that they could generate Covid-19 RNA vaccines that produce a stronger immune response, at a lower dose, in mice.

Adjuvants are molecules commonly used to increase the immune response to vaccines, but they haven’t yet been used in RNA vaccines.  In this study, the MIT researchers engineered both the nanoparticles used to deliver the Covid-19 antigen, and the antigen itself, to boost the immune response, without the need for a separate adjuvant.

If further developed for use in humans, this type of RNA vaccine could help to reduce costs, reduce the dosage needed, and potentially lead to longer-lasting immunity. The researchers’ tests also showed that when delivered intranasally, the vaccine induced a strong immune response when compared to the response elicited by traditional, intramuscular vaccination.

“With intranasal vaccination, you might be able to kill Covid at the mucus membrane, before it gets into your body,” says Daniel Anderson, a professor in MIT’s Department of Chemical Engineering, a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science (IMES), and the senior author of the study. “Intranasal vaccines may also be easier to administer to many people, since they don’t require an injection.”

The researchers believe that the effectiveness of other types of RNA vaccines that are now in development, including vaccines for cancer, could be improved by incorporating similar immune-stimulating properties.

Former MIT postdoc Bowen Li, who is now an assistant professor at the University of Toronto; graduate student Allen Jiang; and former MIT postdoc Idris Raji, who was a research fellow at Boston Children’s Hospital, are the lead authors of the new study, which appears today in Nature Biomedical Engineering. The research team also includes Robert Langer, the David H. Koch Institute Professor at MIT and a member of the Koch Institute, and several other MIT researchers.

Boosting immunity

RNA vaccines consist of a strand of RNA that encodes a viral or bacterial protein, also called an antigen. In the case of Covid-19 vaccines, this RNA codes for a segment of the virus’s spike protein. That RNA strand is packaged in a lipid nanoparticle carrier, which protects the RNA from being broken down in the body and helps it get into cells.

Once delivered into cells, the RNA is translated into proteins that the immune system can detect, generating antibodies and T cells that will recognize the protein if the person later becomes infected with the SARS-CoV-2 virus.

The original Covid-19 RNA vaccines developed by Moderna and Pfizer/BioNTech provoked strong immune responses, but the MIT team wanted to see if they could make them more effective by engineering them to have immune stimulatory properties.

In this study, the researchers employed two different strategies to boost the immune response. For the first, they focused on a protein called C3d, which is part of an arm of the immune response known as the complement system. This set of proteins helps the body fight off infection, and C3d’s role is to bind to antigens and amplify the antibody response to those antigens. For many years, scientists have been evaluating the use of C3d as a molecular adjuvant for vaccines made from proteins, such as the DPT vaccine.  

“With the promise of mRNA technologies being realized with the Covid vaccines, we thought that this would be a fantastic opportunity to see if C3d might also be able to play a role as an adjuvant in mRNA vaccine systems,” Jiang says.

To that end, the researchers engineered the mRNA to encode the C3d protein fused to the antigen, so that both components are produced as one protein by cells that receive the vaccine.

In the second phase of their strategy, the researchers modified the lipid nanoparticles used to deliver the RNA vaccine, so that in addition to helping with RNA delivery, the lipids also intrinsically stimulate a stronger immune response.

To identify lipids that would work best, the researchers created a library of 480 lipid nanoparticles with different types of chemistries. All of these are “ionizable” lipids, which become positively charged when they enter acidic environments. The original Covid RNA vaccines also included some ionizable lipids because they help the nanoparticles to self-assemble with RNA and they help target cells to take up the vaccine.

“We understood that nanoparticles themselves could be immunostimulatory, but we weren't quite sure what the chemistry was that was needed to optimize that response. So instead of trying to make the perfect one, we made a library and evaluated them, and through that we identified some chemistries that seemed to improve their response,” Anderson says.

Toward intranasal vaccines

The researchers tested their new vaccine, which included both RNA-encoded C3d and a top-performing ionizable lipid identified from their library screen, in mice. They found that mice injected with this vaccine produced 10 times more antibodies than mice given unadjuvanted Covid RNA vaccines. The new vaccine also provoked a stronger response among T cells, which play important roles in combating the SARS-CoV-2 virus.

“For the first time, we’ve demonstrated a synergistic boost in immune responses by engineering both the RNA and its delivery vehicles,” Li says. “This prompted us to investigate the feasibility of administering this new RNA vaccine platform intranasally, considering the challenges presented by the mucociliary blanket barrier in the upper airways.”

When the researchers delivered the vaccine intranasally, they observed a similarly strong immune response in the mice. If developed for use in people, an intranasal vaccine could potentially offer enhanced protection against infection because it would generate an immune response within the mucosal tissues that line the nasal passages and lungs. 

Because self-adjuvanting vaccines elicit a stronger response at a lower dose, this approach could also help to reduce the cost of vaccine doses, which might allow them to reach more people, especially in developing nations, the researchers say.

Anderson’s lab is now exploring whether this self-adjuvanting platform might also help boost the immune response of other types of RNA vaccines, including cancer vaccines. Working with health care companies, the researchers also plan to test the effectiveness and safety of these new vaccine formulations in larger animal models, in hopes of eventually testing them in patients.

The research was funded by the National Institutes of Health and Translate Bio.

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.

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.

RNA vaccines against Covid-19 have proven effective at reducing the severity of disease. However, a team of researchers at MIT is working on making them even better. By tweaking the design of the vaccines, the researchers showed that they could generate Covid-19 RNA vaccines that produce a stronger immune response, at a lower dose, in mice.

Adjuvants are molecules commonly used to increase the immune response to vaccines, but they haven’t yet been used in RNA vaccines.  In this study, the MIT researchers engineered both the nanoparticles used to deliver the Covid-19 antigen, and the antigen itself, to boost the immune response, without the need for a separate adjuvant.

If further developed for use in humans, this type of RNA vaccine could help to reduce costs, reduce the dosage needed, and potentially lead to longer-lasting immunity. The researchers’ tests also showed that when delivered intranasally, the vaccine induced a strong immune response when compared to the response elicited by traditional, intramuscular vaccination.

“With intranasal vaccination, you might be able to kill Covid at the mucus membrane, before it gets into your body,” says Daniel Anderson, a professor in MIT’s Department of Chemical Engineering, a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science (IMES), and the senior author of the study. “Intranasal vaccines may also be easier to administer to many people, since they don’t require an injection.”

The researchers believe that the effectiveness of other types of RNA vaccines that are now in development, including vaccines for cancer, could be improved by incorporating similar immune-stimulating properties.

Former MIT postdoc Bowen Li, who is now an assistant professor at the University of Toronto; graduate student Allen Jiang; and former MIT postdoc Idris Raji, who was a research fellow at Boston Children’s Hospital, are the lead authors of the new study, which appears today in Nature Biomedical Engineering. The research team also includes Robert Langer, the David H. Koch Institute Professor at MIT and a member of the Koch Institute, and several other MIT researchers.

Boosting immunity

RNA vaccines consist of a strand of RNA that encodes a viral or bacterial protein, also called an antigen. In the case of Covid-19 vaccines, this RNA codes for a segment of the virus’s spike protein. That RNA strand is packaged in a lipid nanoparticle carrier, which protects the RNA from being broken down in the body and helps it get into cells.

Once delivered into cells, the RNA is translated into proteins that the immune system can detect, generating antibodies and T cells that will recognize the protein if the person later becomes infected with the SARS-CoV-2 virus.

The original Covid-19 RNA vaccines developed by Moderna and Pfizer/BioNTech provoked strong immune responses, but the MIT team wanted to see if they could make them more effective by engineering them to have immune stimulatory properties.

In this study, the researchers employed two different strategies to boost the immune response. For the first, they focused on a protein called C3d, which is part of an arm of the immune response known as the complement system. This set of proteins helps the body fight off infection, and C3d’s role is to bind to antigens and amplify the antibody response to those antigens. For many years, scientists have been evaluating the use of C3d as a molecular adjuvant for vaccines made from proteins, such as the DPT vaccine.  

“With the promise of mRNA technologies being realized with the Covid vaccines, we thought that this would be a fantastic opportunity to see if C3d might also be able to play a role as an adjuvant in mRNA vaccine systems,” Jiang says.

To that end, the researchers engineered the mRNA to encode the C3d protein fused to the antigen, so that both components are produced as one protein by cells that receive the vaccine.

In the second phase of their strategy, the researchers modified the lipid nanoparticles used to deliver the RNA vaccine, so that in addition to helping with RNA delivery, the lipids also intrinsically stimulate a stronger immune response.

To identify lipids that would work best, the researchers created a library of 480 lipid nanoparticles with different types of chemistries. All of these are “ionizable” lipids, which become positively charged when they enter acidic environments. The original Covid RNA vaccines also included some ionizable lipids because they help the nanoparticles to self-assemble with RNA and they help target cells to take up the vaccine.

“We understood that nanoparticles themselves could be immunostimulatory, but we weren't quite sure what the chemistry was that was needed to optimize that response. So instead of trying to make the perfect one, we made a library and evaluated them, and through that we identified some chemistries that seemed to improve their response,” Anderson says.

Toward intranasal vaccines

The researchers tested their new vaccine, which included both RNA-encoded C3d and a top-performing ionizable lipid identified from their library screen, in mice. They found that mice injected with this vaccine produced 10 times more antibodies than mice given unadjuvanted Covid RNA vaccines. The new vaccine also provoked a stronger response among T cells, which play important roles in combating the SARS-CoV-2 virus.

“For the first time, we’ve demonstrated a synergistic boost in immune responses by engineering both the RNA and its delivery vehicles,” Li says. “This prompted us to investigate the feasibility of administering this new RNA vaccine platform intranasally, considering the challenges presented by the mucociliary blanket barrier in the upper airways.”

When the researchers delivered the vaccine intranasally, they observed a similarly strong immune response in the mice. If developed for use in people, an intranasal vaccine could potentially offer enhanced protection against infection because it would generate an immune response within the mucosal tissues that line the nasal passages and lungs. 

Because self-adjuvanting vaccines elicit a stronger response at a lower dose, this approach could also help to reduce the cost of vaccine doses, which might allow them to reach more people, especially in developing nations, the researchers say.

Anderson’s lab is now exploring whether this self-adjuvanting platform might also help boost the immune response of other types of RNA vaccines, including cancer vaccines. Working with health care companies, the researchers also plan to test the effectiveness and safety of these new vaccine formulations in larger animal models, in hopes of eventually testing them in patients.

The research was funded by the National Institutes of Health and Translate Bio.