February 26, 2022
Journal Article

Circulating ACE2-expressing Extracellular Vesicles Block Broad Strains of SARS-CoV-2


The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the pandemic of the coronavirus induced disease 2019 (COVID-19) with 216 million cases and 4.5 million deaths as of September 2021. That has been exacerbated by mutated variants such as a, ß, and ? with high infection rates and increased breakthroughs, resulting in vaccine inefficiencies and resistance to therapeutic monoclonal antibodies. It remains urgent to identify novel therapeutics against broad strains of SARS-CoV-2 and future emerging corona viruses to protect the immune-compromised, unvaccinated, and even vaccinated alike from evolving infectious diseases. One big question is whether we can harness power from human antiviral immunity for such broad therapeutic development. Wild-type SARS-CoV-2 and its variants infect human and other host cells via the entry receptor angiotensin-converting enzyme 2 (ACE2), triggering innate and adaptive immune responses. Herein, we report an increase in circulating extracellular vesicles (EVs) that express ACE2 (evACE2) in plasma of both acute and convalescent COVID-19 patients as part of innate antiviral response associated with severe pathogenesis. Furthermore, evACE2 isolated from both human plasma and engineered EV-producing cell lines neutralizes SARS-CoV-2 infection by competing with cellular ACE2. Notably, evACE2 blocks the binding of the viral spike (S) protein RBD to ACE2+ cells at a 135-fold higher potency than vesicle-free recombinant human ACE2 (rhACE2). Furthermore, evACE2 prevents cell infections by both pseudotyped and authentic SARS-CoV-2 at a 60- to 80-fold higher efficacy than rhACE2; and it protects the hACE2 mice from SARS-CoV-2-induced lung injury and mortality. More importantly, evACE2 inhibits the infection of SARS-CoV-2 variants (a, ß, and d) with an equal or even higher potency than for the WT strain, supporting evACE2 as a broad-spectrum antiviral mechanism for therapeutic development to block the infection of existing and future corona viruses that use ACE2 as a receptor.

Published: February 26, 2022


El-Shennawy L., A.D. Hoffman, N.K. Dashzeveg, K.M. McAndrews, P.J. Mehl, D. Cornish, and Z. Yu, et al. 2022. Circulating ACE2-expressing Extracellular Vesicles Block Broad Strains of SARS-CoV-2. Nature Communications 13, no. 1:Art. No. 405. PNNL-SA-169658. doi:10.1038/s41467-021-27893-2