Engineered extracellular vesicles antagonize SARS-CoV-2 infection by inhibiting mTOR signaling

A G Ibrahim; A Ciullo; C Li; G Garcia; K Peck; K Miyamoto; V Arumugaswami; E Marbán

doi:10.1016/j.bbiosy.2022.100042

Engineered extracellular vesicles antagonize SARS-CoV-2 infection by inhibiting mTOR signaling

Biomater Biosyst. 2022 Jun:6:100042. doi: 10.1016/j.bbiosy.2022.100042. Epub 2022 Feb 13.

Authors

A G Ibrahim¹, A Ciullo¹, C Li¹, G Garcia², K Peck¹, K Miyamoto¹, V Arumugaswami², E Marbán¹

Affiliations

¹ Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, CA, USA.
² Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.

Abstract

Effective treatment approaches for patients with COVID-19 remain limited and are neither curative nor widely applicable. Activated specialized tissue effector extracellular vesicles (ASTEX) derived from genetically-enhanced skin fibroblasts, exert disease-modifying bioactivity in vivo in models of heart and lung injury. Here we report that ASTEX antagonizes SARS-CoV-2 infection and its pathogenic sequelae. In human lung epithelial cells exposed to SARS-CoV-2, ASTEX is cytoprotective and antiviral. Transcriptomic analysis implicated the mammalian target of rapamycin (mTOR) pathway, as infected cells upregulated mTOR signaling and pre-exposure to ASTEX attenuated it. The implication of mTOR signaling was further confirmed using mTOR inhibition and activation, which increased and decreased viral load, respectively. Dissection of ASTEX cargo identifies miRs including miR-16 as potential inhibitors of mTOR signaling. The findings reveal a novel, dual mechanism of action for ASTEX as a therapeutic candidate for COVID-19, with synergistic antiviral and cytoprotective benefits.

Keywords: ASTEX, Activated specialized tissue effector extracellular vesicles; Covid-19; Covid-19, Coronavirus disease 2019; EVs, Extracellular vesicles; Engineered cells; Extracellular vesicles; SARS-CoV-2; SARS-CoV-2, Severe acute respiratory syndrome coronavirus-2; Viral replication; mTOR; mTOR, Mammalian target of rapamycin.

Abstract

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