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.