Red Blood Cell-Derived Extracellular Vesicles Display Endogenous Antiviral Effects and Enhance the Efficacy of Antiviral Oligonucleotide Therapy
Migara Kavishka Jayasinghe, Chang Gao, Gracemary Yap, Brendon Zhi Jie Yeo, Luyen Tien Vu, Douglas Jie Wen Tay, Wen Xiu Loh, Zhen Qin Aw, Huixin Chen, Dai Cao Phung, Dong Van Hoang, Rebecca Carissa Prajogo, Lissa Hooi, Fang Qing Lim, Marco Pirisinu, Chee Keng Mok, Kah Wai Lim, Sze Jing Tang, Kai Sen Tan, Edward Kai‐Hua Chow, Leilei Chen, Anh Tuân Phan, Justin Jang Hann Chu, Minh T. N. Le
Abstract
High Resolution Image Download MS PowerPoint Slide 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.