Red Blood Cell-Derived Extracellular Vesicles Display Endogenous Antiviral Effects and Enhance the Efficacy of Antiviral Oligonucleotide Therapy

Abstract

The COVID-19 pandemic has resulted in a large number of fatalities and, at present, lacks a readily available curative treatment for patients. Here, we demonstrate that unmodified red blood cell-derived extracellular vesicles (RBCEVs) can inhibit SARS-CoV-2 infection in a phosphatidylserine (PS) dependent manner. Using T cell immunoglobulin mucin domain-1 (TIM-1) as an example, we demonstrate that PS receptors on cells can significantly increase the adsorption and infection of authentic and pseudotyped SARS-CoV-2 viruses. RBCEVs competitively inhibit this interaction and block TIM-1-mediated viral entry into cells. We further extend the therapeutic efficacy of this antiviral treatment by loading antisense oligonucleotides (ASOs) designed to target conserved regions of key SARS-CoV-2 genes into RBCEVs. We establish that ASO-loaded RBCEVs are efficiently taken up by cells in vitro and in vivo to suppress SARS-CoV-2 replication. Our findings indicate that this RBCEV-based SARS-CoV-2 therapeutic displays promise as a potential treatment capable of inhibiting SARS-CoV-2 entry and replication.

A Panorama of Extracellular Vesicle Applications: From Biomarker Detection to Therapeutics

“…For example, EVs secreted by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected cells strongly express its nucleocapsid protein to promote a pro-inflammatory response and can transfer its RNA genome to infect EV recipient cells . Conversely, EVs secreted by unmodified red blood cells can attenuate the transmission of SARS-CoV-2 to other cells by competing for phosphatidyl serine receptors employed to promote virus entry, and the antiviral effects of these EVs can be enhanced by loading them with antisense oligonucleotides that target key SARS-CoV-2 genes …”

“… 50 Conversely, EVs secreted by unmodified red blood cells can attenuate the transmission of SARS-CoV-2 to other cells by competing for phosphatidyl serine receptors employed to promote virus entry, and the antiviral effects of these EVs can be enhanced by loading them with antisense oligonucleotides that target key SARS-CoV-2 genes. 51 …”

A comprehensive review of engineered exosomes from the preparation strategy to therapeutic applications

“…21,22 Exosomes, derived from unmodified red blood cells, inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a phosphatidylserine dependent mechanism. 23 Mesenchymal stem cell (MSC)-derived exosomes have demonstrated remarkable efficacy in alleviating necrotizing enterocolitis, improving liver fibrosis and pulmonary function, and providing protection to the heart and kidneys. 24 Exosomes, derived from stem cells, contain biologically active substances, such as therapeutic growth factors and mRNA from maternal cells.…”