Characterization of mRNA-LNP structural features and mechanisms for enhanced mRNA vaccine immunogenicity.

Autor: Wu K; College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, PR China; Zhejiang-California International Nanosystems Institute, Zhejiang University, Hangzhou 310058, PR China., Xu F; HighField Biopharmaceuticals Inc., Hangzhou 310000, PR China., Dai Y; HighField Biopharmaceuticals Inc., Hangzhou 310000, PR China., Jin S; HighField Biopharmaceuticals Inc., Hangzhou 310000, PR China., Zheng A; College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, PR China., Zhang N; Wisdom Lake Academy of Pharmacy, Xi'an Jiaotong-Liverpool University, Suzhou, PR China. Electronic address: Ning.Zhang02@xjtlu.edu.cn., Xu Y; College of Pharmacy, Dali University, Dali 671003, PR China; HighField Biopharmaceuticals Inc., Hangzhou 310000, PR China. Electronic address: yhxu@dali.edu.cn.
Jazyk: angličtina
Zdroj: Journal of controlled release : official journal of the Controlled Release Society [J Control Release] 2024 Dec; Vol. 376, pp. 1288-1299. Date of Electronic Publication: 2024 Nov 13.
DOI: 10.1016/j.jconrel.2024.11.007
Abstrakt: Lipid nanoparticles (LNPs) used for nonviral gene delivery have achieved significant success, particularly in COVID-19 mRNA vaccines. LNPs are routinely characterized by their particle size, polydispersity, and mRNA loading efficiency. However, the internal structure of these particles has not been specified, despite evidence showing that LNPs can be highly heterogeneous, with variations in lipid composition and preparation methods. How these structural features contributed to mRNA LNP vaccine activities is also unclear. In this study, we prepared LNPs with distinctly different internal structures. They were named the emulsion-like LNPs (eLNPs) and membrane-rich LNPs (mLNPs) respectively and compared with the classic "bleb" structure LNPs (cLNPs). The eLNPs contained higher molar percent of the ionizable lipid and lower molar percent of DSPC and cholesterol. The different lipid organization structures lead to varying mRNA delivery activities in vitro and in vivo. After intramuscular injection, eLNPs remained at the injection site and expressed antigens locally. The resulted immune responses had a very fast onset (higher titer at week 2) and lasted longer and stronger (higher titers at week 8) than other LNPs (cLNPs and mLNPs). We hypothesize that the rapid onset and local expression of antigens by muscle cells in the eLNP groups may be favored by the antigen recognition and presentation process, despite the overall mRNA expression activities was not as high especially in liver and other organ. Our data support that eLNPs are potentially the more suitable delivery system for mRNA vaccine due to their high immunogenicity and low systemic toxicity.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: