Inhalation of ACE2-expressing lung exosomes provides prophylactic protection against SARS-CoV-2

Zhenzhen Wang; Shiqi Hu; Kristen D Popowski; Shuo Liu; Dashuai Zhu; Xuan Mei; Junlang Li; Yilan Hu; Phuong-Uyen C Dinh; Xiaojie Wang; Ke Cheng

doi:10.1038/s41467-024-45628-x

Inhalation of ACE2-expressing lung exosomes provides prophylactic protection against SARS-CoV-2

Nat Commun. 2024 Mar 12;15(1):2236. doi: 10.1038/s41467-024-45628-x.

Authors

Zhenzhen Wang^{1

2

3}, Shiqi Hu⁴, Kristen D Popowski^{5

6}, Shuo Liu⁴, Dashuai Zhu⁴, Xuan Mei^{5

6}, Junlang Li⁷, Yilan Hu⁴, Phuong-Uyen C Dinh^{5

6}, Xiaojie Wang^{8

9}, Ke Cheng¹⁰

Affiliations

¹ School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, 511442, P.R. China. zwang@scut.edu.cn.
² Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, NC, 27606, USA. zwang@scut.edu.cn.
³ Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, and North Carolina State University, Raleigh, NC, 27606, USA. zwang@scut.edu.cn.
⁴ Department of Biomedical Engineering, Columbia University, New York, New York, 10032, USA.
⁵ Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, NC, 27606, USA.
⁶ Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, and North Carolina State University, Raleigh, NC, 27606, USA.
⁷ Xsome Biotech Inc., Raleigh, North Carolina, 27607, USA.
⁸ School of Pharmacy, Wenzhou Medical University, Wenzhou, 325035, P.R. China. susanwang1214@wmu.edu.cn.
⁹ Engineering Research Center of the Chinese Ministry of Education for Bioreactor and Pharmaceutical Development, Jilin Agricultural University, Changchun, 130118, P.R. China. susanwang1214@wmu.edu.cn.
¹⁰ Department of Biomedical Engineering, Columbia University, New York, New York, 10032, USA. ke.cheng@columbia.edu.

Abstract

Continued emergence of SARS-CoV-2 variants of concern that are capable of escaping vaccine-induced immunity highlights the urgency of developing new COVID-19 therapeutics. An essential mechanism for SARS-CoV-2 infection begins with the viral spike protein binding to the human ACE2. Consequently, inhibiting this interaction becomes a highly promising therapeutic strategy against COVID-19. Herein, we demonstrate that ACE2-expressing human lung spheroid cells (LSC)-derived exosomes (LSC-Exo) could function as a prophylactic agent to bind and neutralize SARS-CoV-2, protecting the host against SARS-CoV-2 infection. Inhalation of LSC-Exo facilitates its deposition and biodistribution throughout the whole lung in a female mouse model. We show that LSC-Exo blocks the interaction of SARS-CoV-2 with host cells in vitro and in vivo by neutralizing the virus. LSC-Exo treatment protects hamsters from SARS-CoV-2-induced disease and reduced viral loads. Furthermore, LSC-Exo intercepts the entry of multiple SARS-CoV-2 variant pseudoviruses in female mice and shows comparable or equal potency against the wild-type strain, demonstrating that LSC-Exo may act as a broad-spectrum protectant against existing and emerging virus variants.

MeSH terms

Angiotensin-Converting Enzyme 2
Animals
Antibodies, Neutralizing
COVID-19*
Cricetinae
Exosomes*
Female
Humans
Mice
SARS-CoV-2
Spike Glycoprotein, Coronavirus
Tissue Distribution

Substances

Angiotensin-Converting Enzyme 2
Spike Glycoprotein, Coronavirus
Antibodies, Neutralizing
spike protein, SARS-CoV-2

Supplementary concepts

SARS-CoV-2 variants