The goal of nanomedicine is to perform “single-cell medicine,” which is the comprehensive monitoring, control, construction, repair, defense, and improvement of human biological systems at the molecular level using engineered nanodevices and nanostructures operating massively in parallel at the single-cell level.
Penn Medicine researchers have developed a new, more effective method of preventing the body’s own proteins from treating nanomedicines as foreign invaders, by coating the nanoparticles with a coating that suppresses the immune response that dampens the therapy’s effectiveness.
When unmodified nanoparticles are injected into the bloodstream, they are swarmed by immune system elements known as complement proteins, triggering an inflammatory response and preventing the nanoparticles from reaching their therapeutic targets in the body. Researchers have devised some solutions to this problem, but the Penn Medicine team, whose findings were published in Advanced Materials, has invented what may be the best method yet: coating nanoparticles with natural complement activation suppressors.
Nanoparticles are tiny capsules made of proteins or fat-related molecules that serve as delivery vehicles for specific types of treatment or vaccine, typically those containing RNA or DNA. It turned out to be one of those technologies that just works right away and better than expected.
Jacob Brenner
Nanoparticles are tiny capsules made of proteins or fat-related molecules that serve as delivery vehicles for specific types of treatment or vaccine, typically those containing RNA or DNA. mRNA vaccines against COVID-19 are the most well-known examples of nanoparticle-delivered medicines.
“It turned out to be one of those technologies that just works right away and better than expected,” study co-senior author Jacob Brenner, MD, Ph.D., an associate professor of Pulmonary Medicine in the Division of Pulmonary, Allergy, and Critical Care, said.
The Complement Problem
RNA or DNA-based therapies typically require delivery systems to get them through the bloodstream and into target organs. In the past, harmless viruses were frequently used as carriers or “vectors” of these therapies, but nanoparticles are increasingly being regarded as safer alternatives. Nanoparticles can also be tagged with antibodies or other molecules, allowing them to zero in on specific tissues.
Despite its promise, nanoparticle-based medicine has been severely hampered by the complement attack problem. Circulating complement proteins treat nanoparticles as if they were bacteria, coating nanoparticle surfaces and summoning large white blood cells to consume the “invaders.” Researchers have attempted to mitigate the problem by pre-coating nanoparticles with camouflaging molecules, such as the organic compound polyethylene glycol (PEG), which attracts water molecules to form a watery, protective shell around nanoparticles. However, nanoparticles disguised with PEG or other protective substances still attract at least some complement attack.
In general, nanoparticle-based medicines that must travel through the bloodstream to do their work (mRNA COVID-19 vaccines are injected into muscle rather than the bloodstream) have a very low efficiency in reaching their target organs, usually less than 1%.
Taking a Strategy
Brenner and Myerson and their colleagues developed an alternative or add-on approach to protecting nanoparticles in the study, which is based on natural complement-inhibitor proteins that circulate in the blood and attach to human cells to help protect them from complement attack.
In lab-dish experiments, the researchers discovered that coating standard PEG-protected nanoparticles with one of these complement inhibitors, called Factor I, provided significantly better protection from complement attack. The same strategy was used in mice to extend the half-life of standard nanoparticles in the bloodstream, allowing a much higher fraction of them to reach their targets.
“Many bacteria coat themselves with these factors to protect themselves against complement attack, so we decided to borrow that strategy for nanoparticles,” explained co-senior author Jacob Myerson, PhD, a senior research scientist in Penn’s Department of Systems Pharmacology and Translational Therapeutics.
The researchers also demonstrated that attaching Factor I to nanoparticles prevents a potentially fatal hyper-allergic reaction in mouse models of severe inflammatory illness. More testing will be required before nanomedicines containing Factor I can be used in humans, but the researchers believe that attaching the complement-suppressing protein could make nanoparticles safer and more efficient as therapeutic delivery vehicles, allowing them to be used even in critically ill patients.
The researchers intend to develop strategies to protect not only nanomedicines, but also medical devices such as catheters, stents, and dialysis tubing, which are also vulnerable to complement attack. Aside from Factor I, they intend to look into other protective proteins.
“We’re realizing now that there’s a whole world of proteins we can put on the surface of nanoparticles to protect them from immune attack,” Brenner said.
The goal of nanomedicine is to perform “single-cell medicine,” which is the comprehensive monitoring, control, construction, repair, defense, and improvement of human biological systems at the molecular level using engineered nanodevices and nanostructures operating massively in parallel at the single-cell level.
Penn Medicine researchers have developed a new, more effective method of preventing the body’s own proteins from treating nanomedicines as foreign invaders, by coating the nanoparticles with a coating that suppresses the immune response that dampens the therapy’s effectiveness.
When unmodified nanoparticles are injected into the bloodstream, they are swarmed by immune system elements known as complement proteins, triggering an inflammatory response and preventing the nanoparticles from reaching their therapeutic targets in the body. Researchers have devised some solutions to this problem, but the Penn Medicine team, whose findings were published in Advanced Materials, has invented what may be the best method yet: coating nanoparticles with natural complement activation suppressors.
Nanoparticles are tiny capsules made of proteins or fat-related molecules that serve as delivery vehicles for specific types of treatment or vaccine, typically those containing RNA or DNA. It turned out to be one of those technologies that just works right away and better than expected.
Jacob Brenner
Nanoparticles are tiny capsules made of proteins or fat-related molecules that serve as delivery vehicles for specific types of treatment or vaccine, typically those containing RNA or DNA. mRNA vaccines against COVID-19 are the most well-known examples of nanoparticle-delivered medicines.
“It turned out to be one of those technologies that just works right away and better than expected,” study co-senior author Jacob Brenner, MD, PhD, an associate professor of Pulmonary Medicine in the Division of Pulmonary, Allergy, and Critical Care, said.
The Complement Problem
RNA or DNA-based therapies typically require delivery systems to get them through the bloodstream and into target organs. In the past, harmless viruses were frequently used as carriers or “vectors” of these therapies, but nanoparticles are increasingly being regarded as safer alternatives. Nanoparticles can also be tagged with antibodies or other molecules, allowing them to zero in on specific tissues.
Fig: Researchers develop new method to increase effectiveness of nanomedicines
Despite its promise, nanoparticle-based medicine has been severely hampered by the complement attack problem. Circulating complement proteins treat nanoparticles as if they were bacteria, coating nanoparticle surfaces and summoning large white blood cells to consume the “invaders.” Researchers have attempted to mitigate the problem by pre-coating nanoparticles with camouflaging molecules, such as the organic compound polyethylene glycol (PEG), which attracts water molecules to form a watery, protective shell around nanoparticles. However, nanoparticles disguised with PEG or other protective substances still attract at least some complement attack.
In general, nanoparticle-based medicines that must travel through the bloodstream to do their work (mRNA COVID-19 vaccines are injected into muscle rather than the bloodstream) have a very low efficiency in reaching their target organs, usually less than 1%.
Taking a Strategy
Brenner and Myerson and their colleagues developed an alternative or add-on approach to protecting nanoparticles in the study, which is based on natural complement-inhibitor proteins that circulate in the blood and attach to human cells to help protect them from complement attack.
In lab-dish experiments, the researchers discovered that coating standard PEG-protected nanoparticles with one of these complement inhibitors, called Factor I, provided significantly better protection from complement attack. The same strategy was used in mice to extend the half-life of standard nanoparticles in the bloodstream, allowing a much higher fraction of them to reach their targets.
“Many bacteria coat themselves with these factors to protect themselves against complement attack, so we decided to borrow that strategy for nanoparticles,” explained co-senior author Jacob Myerson, PhD, a senior research scientist in Penn’s Department of Systems Pharmacology and Translational Therapeutics.
The researchers also demonstrated that attaching Factor I to nanoparticles prevents a potentially fatal hyper-allergic reaction in mouse models of severe inflammatory illness. More testing will be required before nanomedicines containing Factor I can be used in humans, but the researchers believe that attaching the complement-suppressing protein could make nanoparticles safer and more efficient as therapeutic delivery vehicles, allowing them to be used even in critically ill patients.
The researchers intend to develop strategies to protect not only nanomedicines, but also medical devices such as catheters, stents, and dialysis tubing, which are also vulnerable to complement attack. Aside from Factor I, they intend to look into other protective proteins.
“We’re realizing now that there’s a whole world of proteins we can put on the surface of nanoparticles to protect them from immune attack,” Brenner said.
Researchers Devise a New Way for Increasing the Efficacy of Nanomedicines
The goal of nanomedicine is to perform “single-cell medicine,” which is the comprehensive monitoring, control, construction, repair, defense, and improvement of human biological systems at the molecular level using engineered nanodevices and nanostructures operating massively in parallel at the single-cell level.
Penn Medicine researchers have developed a new, more effective method of preventing the body’s own proteins from treating nanomedicines as foreign invaders, by coating the nanoparticles with a coating that suppresses the immune response that dampens the therapy’s effectiveness.
When unmodified nanoparticles are injected into the bloodstream, they are swarmed by immune system elements known as complement proteins, triggering an inflammatory response and preventing the nanoparticles from reaching their therapeutic targets in the body. Researchers have devised some solutions to this problem, but the Penn Medicine team, whose findings were published in Advanced Materials, has invented what may be the best method yet: coating nanoparticles with natural complement activation suppressors.
Nanoparticles are tiny capsules made of proteins or fat-related molecules that serve as delivery vehicles for specific types of treatment or vaccine, typically those containing RNA or DNA. It turned out to be one of those technologies that just works right away and better than expected.
Jacob Brenner
Nanoparticles are tiny capsules made of proteins or fat-related molecules that serve as delivery vehicles for specific types of treatment or vaccine, typically those containing RNA or DNA. mRNA vaccines against COVID-19 are the most well-known examples of nanoparticle-delivered medicines.
“It turned out to be one of those technologies that just works right away and better than expected,” study co-senior author Jacob Brenner, MD, PhD, an associate professor of Pulmonary Medicine in the Division of Pulmonary, Allergy, and Critical Care, said.
The Complement Problem
RNA or DNA-based therapies typically require delivery systems to get them through the bloodstream and into target organs. In the past, harmless viruses were frequently used as carriers or “vectors” of these therapies, but nanoparticles are increasingly being regarded as safer alternatives. Nanoparticles can also be tagged with antibodies or other molecules, allowing them to zero in on specific tissues.
Fig: Researchers develop new method to increase effectiveness of nanomedicines
Despite its promise, nanoparticle-based medicine has been severely hampered by the complement attack problem. Circulating complement proteins treat nanoparticles as if they were bacteria, coating nanoparticle surfaces and summoning large white blood cells to consume the “invaders.” Researchers have attempted to mitigate the problem by pre-coating nanoparticles with camouflaging molecules, such as the organic compound polyethylene glycol (PEG), which attracts water molecules to form a watery, protective shell around nanoparticles. However, nanoparticles disguised with PEG or other protective substances still attract at least some complement attack.
In general, nanoparticle-based medicines that must travel through the bloodstream to do their work (mRNA COVID-19 vaccines are injected into muscle rather than the bloodstream) have a very low efficiency in reaching their target organs, usually less than 1%.
Taking a Strategy
Brenner and Myerson and their colleagues developed an alternative or add-on approach to protecting nanoparticles in the study, which is based on natural complement-inhibitor proteins that circulate in the blood and attach to human cells to help protect them from complement attack.
In lab-dish experiments, the researchers discovered that coating standard PEG-protected nanoparticles with one of these complement inhibitors, called Factor I, provided significantly better protection from complement attack. The same strategy was used in mice to extend the half-life of standard nanoparticles in the bloodstream, allowing a much higher fraction of them to reach their targets.
“Many bacteria coat themselves with these factors to protect themselves against complement attack, so we decided to borrow that strategy for nanoparticles,” explained co-senior author Jacob Myerson, PhD, a senior research scientist in Penn’s Department of Systems Pharmacology and Translational Therapeutics.
The researchers also demonstrated that attaching Factor I to nanoparticles prevents a potentially fatal hyper-allergic reaction in mouse models of severe inflammatory illness. More testing will be required before nanomedicines containing Factor I can be used in humans, but the researchers believe that attaching the complement-suppressing protein could make nanoparticles safer and more efficient as therapeutic delivery vehicles, allowing them to be used even in critically ill patients.
The researchers intend to develop strategies to protect not only nanomedicines, but also medical devices such as catheters, stents, and dialysis tubing, which are also vulnerable to complement attack. Aside from Factor I, they intend to look into other protective proteins.
“We’re realizing now that there’s a whole world of proteins we can put on the surface of nanoparticles to protect them from immune attack,” Brenner said.
