Neutralization of SARS-CoV-2 pseudovirus using ACE2-engineered extracellular vesicles

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

“…[ 12 ] The most prominent biological nanoparticles are extracellular vesicles (EVs)—nanometer‐scale particles released by all cells which mediate intercellular transfer of biomolecules. [ 18 , 19 ] EVs have recently been investigated as infectious disease decoys [ 20 , 21 , 22 , 23 ] in part because, in contrast to most synthetic vehicles, EVs uniquely exhibit low toxicity and low immunogenicity, [ 19 , 24 , 25 ] and these properties are likely to be of central importance for particles to be administered via sustained infusions or repeat injections, as is envisioned for decoy applications. Although decoy nanoparticles have yet to be evaluated clinically, it seems likely that this approach would be most beneficial for patients experiencing severe or prolonged infections that are not controlled by either their immune system or available antiviral agents.…”

“…[ 27 ] Subsequent work demonstrated efficacy against replication‐competent SARS‐CoV‐2 in vitro [ 22 ] and suggested that ACE2 EVs were safe and effective against pseudotyped virus when delivered intranasally in a rodent model. [ 23 ] Recent work showed that intravenously administered ACE2 EVs lowered the viral load of authentic SARS‐CoV‐2 in a mouse model, reduced the levels of pro‐inflammatory cytokines in lung tissue, and mitigated lung tissue injury. [ 28 ] These studies validated the fundamental concept that decoy EVs could address this disease and raised a number of interesting questions.…”

Multivalent ACE2 engineering—A promising pathway for advanced coronavirus nanomedicine development

“…Also, Zhang et al [129] reported no observable toxicity when sACE2v.2.4 was intravenously administered (twice daily at 0.5 mg/kg) into mice for 5 continuous days. Several other research have consistently found no adverse effect with the use of ACE2 therapeutics [83] , [106] , [115] , [160] , [170] , [209] . Although higher-level clinical assessments are yet to surface, it is anticipated that the human origin of the ACE2 molecule itself may be important for their safe administration.…”

“…The EVs also neutralized SARS-CoV-2 variants (α, β, and δ) and protected transgenic human ACE2 mice from lung injury and death. Similarly, Wu et al [160] extracted ACE2-EVs from culture supernatants of engineered stable HEK293T-ACE2 cells via a differential ultracentrifugation approach. These bioengineered EVs had an average size of 58.5 nm.…”

ACE2‐enriched extracellular vesicles enhance infectivity of live SARS‐CoV‐2 virus

“…Intriguingly, ACE2-expressing EVs have also inspired a competitive inhibition therapy against SARS-CoV-2, which proposes to use these EVs to occupy SARS-CoV-2 S protein S1 domain, with the aim to protect cells from viral infection (Inal, 2020). As demonstrated in several studies that mainly used RBD binding assay and pseudoviruses infection, authentic or engineered ACE2-expressing EVs have been shown to exhibit a potential therapeutic effect to block SARS-CoV-2 infection (Cocozza et al, 2020;Rao et al, 2020;Wu et al, 2022;Xie et al, 2021;Zhang, Jeppesen et al, 2021;Zhang, Huang et al, 2021). It is worth noting that engineered cell-mimicking nanodecoys with ACE2 also employed similar strategy to neutralize SARS-CoV-2 infection (Li et al, 2021;Rao et al, 2020).…”