Nanoengineered Red Blood Cells Loaded with TMPRSS2 and Cathepsin L Inhibitors Block SARS‐CoV‐2 Pseudovirus Entry into Lung ACE2+ Cells

The enzymatic activities of Furin, Transmembrane serine proteinase 2 (TMPRSS2), Cathepsin L (CTSL), and Angiotensin‐converting enzyme 2 (ACE2) receptor binding are necessary for the entry of coronaviruses into host cells. Precise inhibition of these key proteases in ACE2+ lung cells during a viral i...

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Published in:Advanced materials (Weinheim) 2024-04, Vol.36 (15), p.e2310306-n/a
Main Authors: Yang, Hui, Zhou, Jun‐Nian, Zhang, Xue‐Mei, Ling, Dan‐Dan, Sun, Ying‐Bao, Li, Chen‐Yan, Zhou, Qian‐Qian, Shi, Gao‐Na, Wang, Si‐Han, Lin, Xiao‐Song, Fan, Tao, Wang, Hai‐Yang, Zeng, Quan, Jia, Ya‐Li, Xi, Jia‐Fei, Jin, Yi‐Guang, Pei, Xue‐Tao, Yue, Wen
Format: Article
Language:English
Subjects:
ACE2
Angiotensin-Converting Enzyme 2 - metabolism
Animals
Antibodies
Cathepsin L
Cathepsin L - antagonists & inhibitors
Cathepsin L - metabolism
Cell membranes
coronavirus entry
Coronaviruses
COVID-19 - prevention & control
COVID-19 - virology
Erythrocytes
Lung - metabolism
Lungs
Mice
nanoengineered RBCs
Peptide Hydrolases - metabolism
Proteinase
Receptors
SARS-CoV-2 - metabolism
SARS-CoV-2 - pathogenicity
Serine Endopeptidases - metabolism
Serine Proteinase Inhibitors - pharmacology
Serine Proteinase Inhibitors - therapeutic use
Severe acute respiratory syndrome
TMPRSS2
Viral diseases
Viral infections
Viruses
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Summary:The enzymatic activities of Furin, Transmembrane serine proteinase 2 (TMPRSS2), Cathepsin L (CTSL), and Angiotensin‐converting enzyme 2 (ACE2) receptor binding are necessary for the entry of coronaviruses into host cells. Precise inhibition of these key proteases in ACE2+ lung cells during a viral infection cycle shall prevent viral Spike (S) protein activation and its fusion with a host cell membrane, consequently averting virus entry to the cells. In this study, dual‐drug‐combined (TMPRSS2 inhibitor Camostat and CTSL inhibitor E‐64d) nanocarriers (NCs) are constructed conjugated with an anti‐human ACE2 (hACE2) antibody and employ Red Blood Cell (RBC)‐hitchhiking, termed “Nanoengineered RBCs,” for targeting lung cells. The significant therapeutic efficacy of the dual‐drug‐loaded nanoengineered RBCs in pseudovirus‐infected K18‐hACE2 transgenic mice is reported. Notably, the modular nanoengineered RBCs (anti‐receptor antibody+NCs+RBCs) precisely target key proteases of host cells in the lungs to block the entry of Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), regardless of virus variations. These findings are anticipated to benefit the development of a series of novel and safe host‐cell‐protecting antiviral therapies. Dual‐drug‐combined (Camostat and E‐64d) nanocarriers (NCs) are constructed, conjugated with an anti‐hACE2 antibody and employed RBC‐hitchhiking, termed “Nanoengineered RBCs”, for effectively blocking SARS‐CoV‐2 cell entry in the lungs, regardless of virus variations. The nano‐micro system is modular (anti‐receptor antibody + drug‐loaded NCs + RBCs), and the findings will benefit the development of a series of novel and safe host‐cell‐protecting antiviral therapies.
ISSN:0935-9648
1521-4095
DOI:10.1002/adma.202310306