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Canhao Wu, Qin Xu, Huiyuan Wang, Bin Tu, Jiaxin Zeng, Pengfei Zhao, Mingjie Shi, Hong Qiu, Yongzhuo Huang. Neutralization of SARS-CoV-2 pseudovirus using ACE2-engineered extracellular vesicles[J]. Acta Pharmaceutica Sinica B, 2022, 12(3): 1523-1533

Neutralization of SARS-CoV-2 pseudovirus using ACE2-engineered extracellular vesicles
Canhao Wua,b, Qin Xua, Huiyuan Wangb, Bin Tub,c, Jiaxin Zenga,b, Pengfei Zhaob,d, Mingjie Shib, Hong Qiub, Yongzhuo Huangb,c,e,f
a. Artemisinin Research Center, First Clinical School, Guangzhou University of Chinese Medicine, Guangzhou 510450, China;
b. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;
c. Zhongshan Institute for Drug Discovery, SIMM, CAS, Zhongshan 528437, China;
d. Center of Clinical Pharmacology, The Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou 310009, China;
e. NMPA Key Laboratory for Quality Research and Evaluation of Pharmaceutical Excipients, Shanghai 201203, China;
f. Taizhou University, School of Advanced Study, Institute of Natural Medicine and Health Product, Taizhou 318000, China
Abstract:
The spread of coronavirus disease 2019 (COVID-19) throughout the world has resulted in stressful healthcare burdens and global health crises. Developing an effective measure to protect people from infection is an urgent need. The blockage of interaction between angiotensin-converting enzyme 2 (ACE2) and S protein is considered an essential target for anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) drugs. A full-length ACE2 protein could be a potential drug to block early entry of SARS-CoV-2 into host cells. In this study, a therapeutic strategy was developed by using extracellular vesicles (EVs) with decoy receptor ACE2 for neutralization of SARS-CoV-2. The EVs embedded with engineered ACE2 (EVs-ACE2) were prepared; the EVs-ACE2 were derived from an engineered cell line with stable ACE2 expression. The potential effect of the EVs-ACE2 on anti-SARS-CoV-2 was demonstrated by both in vitro and in vivo neutralization experiments using the pseudovirus with the S protein (S-pseudovirus). EVs-ACE2 can inhibit the infection of S-pseudovirus in various cells, and importantly, the mice treated with intranasal administration of EVs-ACE2 can suppress the entry of S-pseudovirus into the mucosal epithelium. Therefore, the intranasal EVs-ACE2 could be a preventive medicine to protect from SARS-CoV-2 infection. This EVs-based strategy offers a potential route to COVID-19 drug development.
Key words:    SARS-CoV-2    COVID-19    Spike protein    Pseudovirus    Extracellular vesicles    ACE2    Intranasal administration    Neutralization   
Received: 2021-06-07     Revised: 2021-08-04
DOI: 10.1016/j.apsb.2021.09.004
Funds: We are thankful for the support of National Special Project for Significant Drugs Development (2018ZX09711002-010-002, China), National Natural Science Foundation of China (81925035 and 81521005, China), Shanghai Sci-Tech Innovation Initiative (19431903100, 18430740800, China), the Shanghai Collaborative Innovation Group of Early Diagnosis and Precise Treatment of Hemangiomas and Vascular Malformations (SSMU-ZDCX20180701, China), the Sanofi-SIBS Yong Faculty Award, and The Youth Innovation Promotion Association. We thank the Molecular Imaging Center and TEM Facility at SIMM for the technical support.
Corresponding author: Huiyuan Wang,E-mai:wanghuiyuan@simm.ac.cn;Hong Qiu,E-mai:hongqiu@simm.ac.cn;Yongzhuo Huang,E-mai:yzhuang@simm.ac.cn     Email:wanghuiyuan@simm.ac.cn;hongqiu@simm.ac.cn;yzhuang@simm.ac.cn
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Canhao Wu
Qin Xu
Huiyuan Wang
Bin Tu
Jiaxin Zeng
Pengfei Zhao
Mingjie Shi
Hong Qiu
Yongzhuo Huang

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