Rapid generation of circulating and mucosal decoy ACE2 using mRNA nanotherapeutics for the potential treatment of SARS-CoV-2
Open accessAbstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters through the airways and infects the lungs, causing lethal pulmonary damage in vulnerable patients. This virus contains spike proteins on its envelope that binds to human angiotensin-converting enzyme 2 (hACE2) expressed on the surface of airway cells, enabling entry of the virus for causing infection 1,2 . In severe cases, the virus enters the circulatory system, contributing to multiorgan failure. Soluble form of hACE2 binds to SARS-CoV-2 spike protein and prevents viral entry into target cells 3 . Moreover, soluble recombinant ACE2 ameliorates lung injury 4 but its short half-life limits its therapeutic utility 5 . Here, we engineered synthetic mRNA to encode a soluble form of hACE2 (hsACE2) to prevent viral infection. Novel lipid nanoparticles (LNPs) were used to package mRNA and transfect mammalian cells for enhanced production of secreted proteins. Intravenously administered LNP led to hepatic delivery of the mRNA. This elicited secretion of hsACE2 into the blood circulation within 2 h, and levels of circulating hsACE2 peaked at 6 h and gradually decreased over several days. Since the primary site of entry and pathogenesis for SARS-CoV-2 is the lungs, we instilled LNPs into the lungs and were able to detect hsACE2 in the bronchoalveolar lavage fluid within 24 h and lasted for 48 h. Through co-immunoprecipitation, we found that mRNA-generated hsACE2 was able to bind with the receptor binding domain of the SARS-CoV-2 spike protein. Furthermore, hsACE2 was able to strongly inhibit (over 90%) SARS-CoV-2 pseudovirus infection. Our proof of principle study shows that mRNA-based nanotherapeutics can be potentially deployed for pulmonary and extrapulmonary neutralization of SARS-CoV-2 and open new treatment opportunities for COVID-19.
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Lipid nanoparticle-mRNA formulations have been applied to produce therapeutic proteins or antibodies, to edit virus genomes and to engineer immune cells.
“In addition, lipid nanoparticle–mRNA formulations have been applied to produce therapeutic proteins or antibodies39,75,145,146, to edit virus genomes105 and to engineer immune cells136.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [75]
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- Authors
- Kim, J., Mukherjee, A., Nelson, D., Jozic, A., & Sahay, G.
- Affiliations
- Oregon State University (US)
- Corresponding author
- Sahay, Gaurav
- Venue
- bioRxiv (Cold Spring Harbor Laboratory)
- Publisher
- openRxiv
- Published
- 2020-07-25
- PMC
- PMC7386491
- OpenAlex
- W3045163071
- Cited by
- 28
- References
- 44
- Citations by year
- 2024: 1 · 2023: 2 · 2022: 11 · 2021: 12 · 2020: 2
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion)
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Keywords
- SARS-CoV-2, COVID-19 pandemic, soluble ACE2, lipid nanoparticles, mucosal delivery, pulmonary drug delivery, bronchoalveolar lavage
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