TY - JOUR
T1 - Characterization of mRNA-LNP structural features and mechanisms for enhanced mRNA vaccine immunogenicity
AU - Wu, Kangzeng
AU - Xu, Fengwei
AU - Dai, Yongchao
AU - Jin, Shanshan
AU - Zheng, Anjie
AU - Zhang, Ning
AU - Xu, Yuhong
N1 - Publisher Copyright:
© 2024 Elsevier B.V.
PY - 2024/12
Y1 - 2024/12
N2 - 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.
AB - 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.
KW - Delivery
KW - Immunogenicity
KW - LNPs
KW - mRNA vaccine
KW - Structure
UR - http://www.scopus.com/inward/record.url?scp=85208683390&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2024.11.007
DO - 10.1016/j.jconrel.2024.11.007
M3 - Article
C2 - 39522562
AN - SCOPUS:85208683390
SN - 0168-3659
VL - 376
SP - 1288
EP - 1299
JO - Journal of Controlled Release
JF - Journal of Controlled Release
ER -