Vesicle-Based ACE2 Nanoparticle Decoys
While this review has focused on soluble ACE2 receptors and their associated Ig-fusions, work has also been done utilizing membrane-anchored ACE2. These decoys are based on cell-derived vesicles or fabricated nanoparticles derived from cells expressing membrane-embedded ACE285,86,87. Extracellular vesicles produced from cells over-expressing ACE2 together with TMPRSS2—which is required for membrane fusion following ACE2/S binding21—were more effective at neutralizing pseudotyped viruses than purified sACE2, perhaps because of inbuilt avidity from high density receptor display86. TMPRSS2 was required for optimum activity, and it is possible bound viruses fused with the vesicles, effectively creating irreversible neutralization. Vesicles have been further functionalized by the use of membranes from monocytes that naturally express cytokine receptors, such that both virus and cytokines are sequestered on the nanoparticle surface87. Inhibited cytokine signaling might ameliorate potentially life-threatening inflammatory responses associated with severe COVID-19. Cytokine neutralization activity was confirmed in vivo by suppressed inflammation in a lipopolysaccharide-induced lung injury model in mice. While vesicle-based nanoparticles are scientifically exciting and show efficacy for virus and cytokine neutralization, they will almost certainly suffer a tortuous regulatory pathway to the clinic due to composition heterogeneity and safety concerns.