New Coating Makes the Nanomedicine Go Down
In nanomedicine, immune reactions against the nanoparticles that contain the medicine or vaccine, reducing its effectiveness. Researchers have now come up with a new method to prevent the body from treating nanomedicines like foreign invaders, by covering those nanoparticles with a coating to suppress the immune response.
As soon as they are injected into the bloodstream, unmodified nanoparticles are swarmed by complement proteins, triggering an inflammatory response and preventing the nanoparticles from reaching their treatment targets. Penn Medicine researchers, whose findings are published in Advanced Materials, have devised a coating for nanoparticles that suppresses complement activation.
Nanoparticles are tiny capsules, typically made from proteins or fat-related molecules, that contain certain types of treatment or vaccine. The best-known examples of nanoparticle-delivered medicines are mRNA COVID vaccines.
“It turned out to be one of those technologies that just works right away and better than anticipated,” said study co-senior author Jacob Brenner, MD, PhD.
RNA- or DNA-based therapies generally need delivery systems to get them through the bloodstream into target organs. Harmless viruses often have been used as carriers or “vectors” of these therapies, but nanoparticles are increasingly considered safer alternatives. Nanoparticles also can be tagged with antibodies or other molecules that make them hone in precisely on targeted tissues.
The complement attack problem has been a serious impediment to nanomedicine. Circulating complement proteins treat nanoparticles as if they were bacteria, immediately coating nanoparticle surfaces and summoning macrophages to engulf them. Researchers have attempted to reduce the problem by pre-coating nanoparticles with camouflaging molecules, such as forming a watery, protective shell around nanoparticles using polyethylene glycol (PEG).
But nanoparticles camouflaged with substances like PEG still draw at least some complement attack. In general, nanoparticle-based medicines that move through the bloodstream (mRNA COVID vaccines are injected into muscle, not the bloodstream) have had a very low efficiency in getting to their target organs, usually under 1%.
In the study, the researchers came up with a new approach to protect nanoparticles, based on natural complement-inhibitor proteins that circulate in the blood, attaching to human cells to help protect them from complement attack.
In vitro tests using standard PEG-protected nanoparticles with one of these complement inhibitors, called Factor I, provided dramatically better protection from complement attack. In mice, the same strategy prolonged the half-life of standard nanoparticles in the bloodstream, allowing a much larger fraction of them to reach their targets.
“Many bacteria also coat themselves with these factors to protect against complement attack, so we decided to borrow that strategy for nanoparticles,” said co-senior author Jacob Myerson, PhD, a senior research scientist in the Department of Systems Pharmacology and Translational Therapeutics at Penn.
In a set of experiments in mouse models of severe inflammatory illness, the researchers also showed that attaching Factor I to nanoparticles prevents the hyper-allergic reaction that otherwise could be fatal.
Further testing will be needed before nanomedicines incorporating Factor I can be used in people, but in principle, the researchers said, attaching the complement-suppressing protein could make nanoparticles safer and more efficient as therapeutic delivery vehicles so that they could be used even in severely ill patients.
The researchers now plan other protective strategies for medical devices, such as catheters, stents and dialysis tubing, which are similarly susceptible to complement attack. They also plan to investigate other protective proteins.
“We’re recognising now that there’s a whole world of proteins that we can put on the surface of nanoparticles to defend them from immune attack,” Dr Brenner said.
