Engineering Extracellular Vesicles Enriched with Palmitoylated ACE2 as COVID-19 Therapy


Posted: 2021-10-19 19:00:00
. 2021 Oct 19;e2103471. doi: 10.1002/adma.202103471. Online ahead of print. Feng Xie 1 2 , Peng Su 3 , Ting Pan 4 , Xiaoxue Zhou 3 , Heyu Li 3 , Huizhe Huang 5 , Aijun Wang 6 , Fangwei Wang 3 , Jun Huang 3 , Haiyan Yan 1 , Linghui Zeng 1 , Long Zhang 3 , Fangfang Zhou 2 Affiliations Expand Affiliations 1 School of Medicine, Zhejiang University City College, Hangzhou, 310015, China. 2 Institutes of Biology and Medical Science, Soochow University, Suzhou, 215123, China. 3 MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China. 4 Center for Infection and Immunity Studies, School of Medicine, Sun Yat-sen University, Shenzhen, 518107, China. 5 Faculty of Basic Medical Sciences, Chongqing Medical University, Medical College Road 1, Chongqing, 400016, China. 6 Department of Surgery, School of Medicine, UC Davis, Davis, CA, 95817, USA. Item in Clipboard Feng Xie et al. Adv Mater. 2021. Show details Display options Display options Format . 2021 Oct 19;e2103471. doi: 10.1002/adma.202103471. Online ahead of print. Authors Feng Xie 1 2 , Peng Su 3 , Ting Pan 4 , Xiaoxue Zhou 3 , Heyu Li 3 , Huizhe Huang 5 , Aijun Wang 6 , Fangwei Wang 3 , Jun Huang 3 , Haiyan Yan 1 , Linghui Zeng 1 , Long Zhang 3 , Fangfang Zhou 2 Affiliations 1 School of Medicine, Zhejiang University City College, Hangzhou, 310015, China. 2 Institutes of Biology and Medical Science, Soochow University, Suzhou, 215123, China. 3 MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China. 4 Center for Infection and Immunity Studies, School of Medicine, Sun Yat-sen University, Shenzhen, 518107, China. 5 Faculty of Basic Medical Sciences, Chongqing Medical University, Medical College Road 1, Chongqing, 400016, China. 6 Department of Surgery, School of Medicine, UC Davis, Davis, CA, 95817, USA. Item in Clipboard CiteDisplay options Display options Format Abstract Angiotensin converting enzyme 2 (ACE2) is a key receptor present on cell surfaces that directly interacts with the viral spike (S) protein of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). It is proposed that inhibiting this interaction can be promising in treating COVID-19. Here, the presence of ACE2 in extracellular vesicles (EVs) is reported and the EV-ACE2 levels are determined by protein palmitoylation. The Cys141 and Cys498 residues on ACE2 are S-palmitoylated by zinc finger DHHC-Type Palmitoyltransferase 3 (ZDHHC3) and de-palmitoylated by acyl protein thioesterase 1 (LYPLA1), which is critical for the membrane-targeting of ACE2 and their EV secretion. Importantly, by fusing the S-palmitoylation-dependent plasma membrane (PM) targeting sequence with ACE2, EVs enriched with ACE2 on their surface (referred to as PM-ACE2-EVs) are engineered. It is shown that PM-ACE2-EVs can bind to the SARS-CoV-2 S-RBD with high affinity and block its interaction with cell surface ACE2 in vitro. PM-ACE2-EVs show neutralization potency against pseudotyped and authentic SARS-CoV-2 in human ACE2 (hACE2) transgenic mice, efficiently block viral load of authentic SARS-CoV-2, and thus protect host against SARS-CoV-2-induced lung inflammation. The study provides an efficient engineering protocol for constructing a promising, novel biomaterial for application in prophylactic and therapeutic treatments against COVID-19. Keywords: ACE2; SARS-CoV-2; extracellular vesicles; palmitoylation. © 2021 The Authors. Advanced Materials published by Wiley-VCH GmbH. References P. Zhou, X. L. Yang, X. G. Wang, B. Hu, L. Zhang, W. Zhang, H. R. Si, Y. Zhu, B. Li, C. L. Huang, H. D. Chen, J. Chen, Y. Luo, H. Guo, R. D. Jiang, M. Q. Liu, Y. Chen, X. R. Shen, X. Wang, X. S. Zheng, K. Zhao, Q. J. Chen, F. Deng, L. L. Liu, B. Yan, F. X. Zhan, Y. Y. Wang, G. F. Xiao, Z. L. Shi, Nature 2020, 579, 270. N. Zhu, D. Zhang, W. Wang, X. Li, B. Yang, J. Song, X. Zhao, B. Huang, W. Shi, R. Lu, P. Niu, F. Zhan, X. Ma, D. Wang, W. Xu, G. Wu, G. F. Gao, W. Tan, N. Engl. J. Med. 2020, 382, 727. V. Coronaviridae, Nat. Microbiol. 2020, 5, 536. T. S. Fung, D. X. Liu, Annu. Rev. Microbiol. 2019, 73, 529. P. S. Masters, Adv. Virus Res. 2006, 66, 193. Show all 79 references [x] Cite Copy Format: Send To [x]

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