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

  • ACS Nano. 2023 Oct 18. doi: 10.1021/acsnano.3c06803.
Migara K Jayasinghe  1  2 ,  Chang Gao  1  2 ,  Gracemary Yap  1  2 ,  Brendon Zhi Jie Yeo  1  2 ,  Luyen Tien Vu  1  2 ,  Douglas Jie Wen Tay  3  4 ,  Wen Xiu Loh  1  2 ,  Zhen Qin Aw  3  4 ,  Huixin Chen  3  4 ,  Dai Cao Phung  1  2 ,  Dong Van Hoang  1 ,  Rebecca Carissa Prajogo  1  2 ,  Lissa Hooi  5 ,  Fang Qing Lim  1 ,  Marco Pirisinu  6 ,  Chee Keng Mok  3  4 ,  Kah Wai Lim  7 ,  Sze Jing Tang  5 ,  Kai Sen Tan  3  4 ,  Edward Kai-Hua Chow  1  5 ,  Leilei Chen  5  8 ,  Anh Tuan Phan  7 ,  Justin Jang Hann Chu  3  4  9 ,  Minh Tn Le  1  2  9
Affiliations
  • 1. Institute for Digital Medicine and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Singapore 117600, Singapore.
  • 2. Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, Singapore 119228, Singapore.
  • 3. Infectious Diseases Translational Research Programme and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Singapore 117545, Singapore.
  • 4. Biosafety Level 3 Core Facility, Yong Loo Lin School of Medicine, National University of Singapore, 14 Medical Drive, Singapore 117599, Singapore.
  • 5. Cancer Science Institute, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Singapore 117599, Singapore.
  • 6. Department of Biomedical Sciences, Jockey Club College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong SAR 999077, China.
  • 7. Division of Physics & Applied Physics, School of Physical & Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link, Singapore 637371, Singapore.
  • 8. Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Singapore 117594, Singapore.
  • 9. Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, 61 Biopolis Drive, Singapore 138673, Singapore.
PMID: 37852618 DOI: 10.1021/acsnano.3c06803
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.

Keywords
SARS-CoV-2; antisense oligonucleotides; apoptotic mimicry; extracellular vesicles; viral inhibition.
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