Secreted Expression of mRNA-Encoded Truncated ACE2 Variants for SARS-CoV-2 via Lipid-Like Nanoassemblies.
Adv Mater
; 33(34): e2101707, 2021 Aug.
Article
in English
| MEDLINE | ID: covidwho-1316189
ABSTRACT
The transfer of foreign synthetic messenger RNA (mRNA) into cells is essential for mRNA-based protein-replacement therapies. Prophylactic mRNA COVID-19 vaccines commonly utilize nanotechnology to deliver mRNA encoding SARS-CoV-2 vaccine antigens, thereby triggering the body's immune response and preventing infections. In this study, a new combinatorial library of symmetric lipid-like compounds is constructed, and among which a lead compound is selected to prepare lipid-like nanoassemblies (LLNs) for intracellular delivery of mRNA. After multiround optimization, the mRNA formulated into core-shell-structured LLNs exhibits more than three orders of magnitude higher resistance to serum than the unprotected mRNA, and leads to sustained and high-level protein expression in mammalian cells. A single intravenous injection of LLNs into mice achieves over 95% mRNA translation in the spleen, without causing significant hematological and histological changes. Delivery of in-vitro-transcribed mRNA that encodes high-affinity truncated ACE2 variants (tACE2v mRNA) through LLNs induces elevated expression and secretion of tACE2v decoys, which is able to effectively block the binding of the receptor-binding domain of the SARS-CoV-2 to the human ACE2 receptor. The robust neutralization activity in vitro suggests that intracellular delivery of mRNA encoding ACE2 receptor mimics via LLNs may represent a potential intervention strategy for COVID-19.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Phosphatidylethanolamines
/
RNA, Messenger
/
Nanoparticles
/
Galactosidases
/
COVID-19 Vaccines
/
SARS-CoV-2
Type of study:
Prognostic study
Topics:
Vaccines
/
Variants
Limits:
Animals
/
Female
/
Humans
Language:
English
Journal:
Adv Mater
Journal subject:
Biophysics
/
Chemistry
Year:
2021
Document Type:
Article
Affiliation country:
Adma.202101707
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