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Researchers devise a novel way for improving the efficacy of nanomedicines.

Penn Medicine researchers have developed a new, more effective means of avoiding the body's own proteins from mistaking nanomedicines for foreign invaders by coating them with a coating that suppresses the immune response that reduces the therapy's efficiency.

Unmodified nanoparticles are swarmed by immune system elements called complement proteins when injected into the bloodstream, creating an inflammatory response and preventing the nanoparticles from reaching their therapeutic objectives in the body. Researchers have come up with a few solutions to this problem, but the Penn Medicine team, whose findings were published in Advanced Materials, has come up with what may be the finest solution yet: coating nanoparticles with natural complement activation suppressors.

Nanoparticles are microscopic capsules made of proteins or fat-related compounds that are used as delivery vehicles for specific treatments or vaccines, mainly those containing RNA or DNA. mRNA vaccines against COVID-19 are the most well-known instances of nanoparticle-delivered therapeutics.

"It turned out to be one of those technologies that just works right away and better than expected," said Jacob Brenner, MD, PhD, an associate professor of pulmonology in the Division of Pulmonary, Allergy, and Critical Care.

The Complement Issue

Therapies based on RNA or DNA typically require delivery mechanisms to get them into target organs through the bloodstream. In the past, harmless viruses were frequently utilised as carriers or "vectors" for these therapies, but nanoparticles are increasingly being seen as a safer option. Nanoparticles can also be labelled with antibodies or other molecules to help them focus on certain organs.

Despite its potential, the complement attack problem has severely hampered nanoparticle-based treatment. Complement proteins in the blood treat nanoparticles like bacteria, covering them quickly and calling big white blood cells to swallow up the "invaders." They've tried to mitigate the problem by pre-coating nanoparticles with camouflaging compounds like polyethylene glycol, which attracts water molecules and forms a watery, protective shell around nanoparticles. Nanoparticles that have been disguised with PEG or other protective substances still attract complement attack. In general, nanoparticle-based treatments that must travel through the bloodstream to perform their functions (mRNA COVID-19 vaccinations are injected into muscle, not the bloodstream) have a very low effectiveness in reaching their target organs, typically less than 1%.

Taking a Strategy 

Brenner and Myerson's team devised an alternate or add-on technique to protect nanoparticles in the study, based on natural complement-inhibitor proteins that circulate in the bloodstream and connect to human cells to protect them from complement attack.

The researchers discovered that covering ordinary PEG-protected nanoparticles with one of these complement inhibitors, termed Factor I, significantly improved complement protection in lab dishes. The similar method was used in mice to extend the half-life of conventional nanoparticles in the bloodstream, allowing a substantially higher percentage of them to reach their destinations.

"We decided to borrow that strategy for nanoparticles because many bacteria coat themselves with these factors to protect themselves against complement attack," said 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 adding Factor I to nanoparticles inhibits the hyper-allergic reaction that could be lethal in mice models of severe inflammatory disease.

Before nanomedicines incorporating Factor X become available, more testing will be required. I can be used in people, but linking the complement-suppressing protein to nanoparticles could make them safer and more efficient as therapeutic delivery vehicles, allowing them to be utilised even in critically ill patients, according to the researchers.

The researchers are currently working on techniques to safeguard not only nanomedicines, but also medical devices including catheters, stents, and dialysis tubing, which are equally vulnerable to complement attack. Aside from Factor I, they want to look at other protective proteins.

"We're realising now that we can place a whole world of proteins on the surface of nanoparticles to protect them from immune attack," Brenner said.


Zhicheng Wang, Elizabeth D. Hood, Jia Nong, Jing Ding, Oscar A. Marcos‐Contreras, Patrick M. Glassman, Kathryn M. Rubey, Michael Zaleski, Carolann L. Espy, Damodara Gullipali, Takashi Miwa, Vladimir R. Muzykantov, Wen‐Chao Song, Jacob W. Myerson, Jacob S. Brenner. Combating Complement's Deleterious Effects on Nanomedicine by Conjugating Complement Regulatory Proteins to Nanoparticles. Advanced Materials, 2022; 2107070 DOI: 10.1002/adma.202107070

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