Circulating ACE2-expressing extracellular vesicles block broad strains of SARS-CoV-2

Lamiaa El-Shennawy, Andrew D. Hoffmann, Nurmaa Khund Dashzeveg, Kathleen M. McAndrews, Paul J. Mehl, Daphne Cornish, Zihao Yu, Valerie L. Tokars, Vlad Nicolaescu, Anastasia Tomatsidou, Chengsheng Mao, Christopher J. Felicelli, Chia Feng Tsai, Carolina Ostiguin, Yuzhi Jia, Lin Li, Kevin Furlong, Jan Wysocki, Xin Luo, Carolina F. RuivoDaniel Batlle, Thomas J. Hope, Yang Shen, Young Kwang Chae, Hui Zhang, Valerie S. LeBleu, Tujin Shi, Suchitra Swaminathan, Yuan Luo, Dominique Missiakas, Glenn C. Randall, Alexis R. Demonbreun, Michael G. Ison, Raghu Kalluri, Deyu Fang, Huiping Liu*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

62 Scopus citations


The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the pandemic of the coronavirus induced disease 2019 (COVID-19) with evolving variants of concern. It remains urgent to identify novel approaches against broad strains of SARS-CoV-2, which infect host cells via the entry receptor angiotensin-converting enzyme 2 (ACE2). Herein, we report an increase in circulating extracellular vesicles (EVs) that express ACE2 (evACE2) in plasma of COVID-19 patients, which levels are associated with severe pathogenesis. Importantly, evACE2 isolated from human plasma or cells neutralizes SARS-CoV-2 infection by competing with cellular ACE2. Compared to vesicle-free recombinant human ACE2 (rhACE2), evACE2 shows a 135-fold higher potency in blocking the binding of the viral spike protein RBD, and a 60- to 80-fold higher efficacy in preventing infections by both pseudotyped and authentic SARS-CoV-2. Consistently, evACE2 protects the hACE2 transgenic mice from SARS-CoV-2-induced lung injury and mortality. Furthermore, evACE2 inhibits the infection of SARS-CoV-2 variants (α, β, and δ) with equal or higher potency than for the wildtype strain, supporting a broad-spectrum antiviral mechanism of evACE2 for therapeutic development to block the infection of existing and future coronaviruses that use the ACE2 receptor.

Original languageEnglish (US)
Article number405
JournalNature communications
Issue number1
StatePublished - Dec 2022

ASJC Scopus subject areas

  • Physics and Astronomy(all)
  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)


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