They could look like cells and act like cells. But a potential new treatment for COVID-19 is actually a cleverly disguised trickster, which attracts viruses and binds them, rendering them inactive.
As the ever-evolving SARS-CoV-2 virus begins to evade once-promising treatments, such as monoclonal antibody therapies, researchers have become more interested in these “decoy” nanoparticles. Mimicking normal cells, the decoy nanoparticles absorb viruses like a sponge, preventing them from infecting the rest of the body.
In a new study, synthetic biologists at Northwestern University set out to elucidate the design rules needed to make decoy nanoparticles effective and resistant to viral escape. After designing and testing various iterations, the researchers identified a wide range of decoys –; all manufacturable using different methods -; which were incredibly effective against the original virus as well as the mutant variants.
In fact, decoy nanoparticles were up to 50 times more effective at inhibiting naturally occurring viral mutants, compared to traditional protein-based inhibitor drugs. When tested against a viral mutant engineered to resist such treatments, the decoy nanoparticles were up to 1,500 times more effective at inhibiting infection.
Although much more research and clinical evaluations are needed, researchers believe that decoy nanoparticle infusions could one day be used to treat patients with severe or prolonged viral infections.
The study was published late last week (April 7) in the journal Small. In the paper, the team tested decoy nanoparticles against the parent virus SARS-CoV-2 and five variants (including beta, delta, delta-plus and lambda) in cell culture.
We have shown that decoy nanoparticles are effective inhibitors of all these different viral variants. Even variants that escape other drugs have not escaped our decoy nanoparticles.”
Joshua Leonard of Northwestern, study co-lead author
“As we conducted the study, different variants continued to emerge around the world,” added Neha Kamat of Northwestern, co-lead author of the study. “We kept testing our lures against newer variants, and they kept working. It’s very effective.”
Leonard is an associate professor of chemical and biological engineering at Northwestern’s McCormick School of Engineering. Kamat is an assistant professor of biomedical engineering at McCormick. Both are key members of Northwestern’s Center for Synthetic Biology.
“Evolutionary Rock and the Anvil”
As the SARS-CoV-2 virus has mutated to create new variants, some treatments have become less effective in fighting the ever-evolving virus. Just last month, the US Food and Drug Administration (FDA) suspended several monoclonal antibody treatments, for example, due to their failure against the BA.2 omicron subvariant.
But even where treatments fail, the decoy nanoparticles in the new study have never lost their effectiveness. Leonard said it was because the decoys put SARS-CoV-2 “between an evolutionary rock and a hard place.”
SARS-CoV-2 infects human cells by binding its infamous spike protein to the human angiotensin converting enzyme 2 (ACE2) receptor. A cell surface protein, ACE2 provides an entry point for the virus.
To design decoy nanoparticles, the Northwestern team used nanoparticles (extracellular vesicles) naturally released by all cell types. They engineered cells producing these particles to overexpress the ACE2 gene, leading to numerous ACE2 receptors on the surfaces of the particles. When the virus came into contact with the decoy, it bound tightly to these receptors rather than real cells, rendering the virus unable to infect the cells.
“For the virus to enter a cell, it must bind to the ACE2 receptor,” Leonard said. “Decoy nanoparticles present an evolutionary challenge for SARS-CoV-2. The virus would have to find an entirely different way to enter cells to avoid the need to use ACE2 receptors. There is no obvious evolutionary escape route.
In addition to being effective against drug-resistant viruses, decoy nanoparticles have several other advantages. Because they are biological (rather than synthetic) materials, nanoparticles are less likely to trigger an immune response, which causes inflammation and can interfere with drug efficacy. They also exhibit low toxicity, which makes them particularly well suited for use in prolonged or repeated administration for the treatment of seriously ill patients.
When the COVID-19 pandemic began, researchers and clinicians experienced a troubling gap between discovering the virus and developing new drugs to treat it. For the next pandemic, decoy nanoparticles could provide fast and effective treatment before vaccines are developed.
“The decoy strategy is one of the most immediate things you can try,” Leonard said. “As soon as you know the receptor used by the virus, you can start building decoy particles with those receptors. We could potentially accelerate an approach like this to reduce serious illness and death in the crucial early stages of future viral pandemics.
The study, “Elucidating design principles for engineering cell-derived vesicles to inhibit SARS-CoV-2 infection,” was supported by the National Science Foundation (grant numbers 1844219 and 1844336) and a gift from Kairos Ventures.
Gunnels, TF, et al. (2022) Elucidating Design Principles for Engineering Cell-Derived Vesicles to Inhibit SARS-CoV-2 Infection. Small. doi.org/10.1002/smll.202200125.