Elucidating Design Principles for Engineering Cell‐Derived Vesicles to Inhibit SARS‐CoV‐2 Infection

Abstract

The ability of pathogens to develop drug resistance is a global health challenge. Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) presents an urgent need wherein several variants of concern resist neutralization by monoclonal antibody (mAb) therapies and vaccine‐induced sera. Decoy nanoparticles—cell‐mimicking particles that bind and inhibit virions—are an emerging class of therapeutics that may overcome such drug resistance challenges. To date, quantitative understanding as to how design features impact performance of these therapeutics is lacking. To address this gap, this study presents a systematic, comparative evaluation of various biologically derived nanoscale vesicles, which may be particularly well suited to sustained or repeated administration in the clinic due to low toxicity, and investigates their potential to inhibit multiple classes of model SARS‐CoV‐2 virions. A key finding is that such particles exhibit potent antiviral efficacy across multiple manufacturing methods, vesicle subclasses, and virus‐decoy binding affinities. In addition, these cell‐mimicking vesicles effectively inhibit model SARS‐CoV‐2 variants that evade mAbs and recombinant protein‐based decoy inhibitors. This study provides a foundation of knowledge that may guide the design of decoy nanoparticle inhibitors for SARS‐CoV‐2 and other viral infections.

Meet changes with constancy: Defence, antagonism, recovery, and immunity roles of extracellular vesicles in confronting SARS‐CoV‐2

“…In addition, mutant SARS‐CoV‐2 strains that were resistant to mAb antibodies and sACE2 inhibitors, as well as Delta and Lambda, were all effectively inhibited by this nanodecoy strategy. This study shows that the antiviral effects of a nanodecoy containing ACE2 may be unaffected by the type of EVs or the purification technique used, and that, given the benefits, NVs could be a good substitute (Gunnels et al., 2022).…”

Exosomes in COVID‐19 infection: Focus on role in diagnosis, pathogenesis, immunity, and clinical trials

“…It has been proposed that excess soluble ACE2 could bind to the S spike protein on the SARS-COV-2 virus, neutralizing the virus and preventing its fusion to the host membrane. Interestingly, Gunnels et al (2022) with low amounts of ACE2-positive exosomes, suggesting the protective efficacy of ACE2-positive exosomes (Ching et al, 2022).…”

Using nanomaterials to address SARS-CoV-2 variants through development of vaccines and therapeutics

“…New COVID-19 VOCs provide challenges when designing therapeutics employing decoy strategies. Gunnels et al identified a Beta mutant consisting of three mutations in its receptor binding domain making it resistant to FDA approved mAbs (K417N, E484K, N501Y) that inhibit its interaction with the host ACE2 (Gunnels et al, 2022). These mutations increase affinity of the spike protein for the host ACE2 by three folds.…”