Ionization and structural properties of mRNA lipid nanoparticles influence expression in intramuscular and intravascular administration.
Commun Biol
; 4(1): 956, 2021 08 11.
Article
in English
| MEDLINE | ID: covidwho-1354120
ABSTRACT
Lipid Nanoparticles (LNPs) are used to deliver siRNA and COVID-19 mRNA vaccines. The main factor known to determine their delivery efficiency is the pKa of the LNP containing an ionizable lipid. Herein, we report a method that can predict the LNP pKa from the structure of the ionizable lipid. We used theoretical, NMR, fluorescent-dye binding, and electrophoretic mobility methods to comprehensively measure protonation of both the ionizable lipid and the formulated LNP. The pKa of the ionizable lipid was 2-3 units higher than the pKa of the LNP primarily due to proton solvation energy differences between the LNP and aqueous medium. We exploited these results to explain a wide range of delivery efficiencies in vitro and in vivo for intramuscular (IM) and intravascular (IV) administration of different ionizable lipids at escalating ionizable lipid-to-mRNA ratios in the LNP. In addition, we determined that more negatively charged LNPs exhibit higher off-target systemic expression of mRNA in the liver following IM administration. This undesirable systemic off-target expression of mRNA-LNP vaccines could be minimized through appropriate design of the ionizable lipid and LNP.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
RNA, Messenger
/
Gene Expression
/
Nanoparticles
/
Ions
/
Lipids
Type of study:
Prognostic study
Topics:
Vaccines
Limits:
Animals
/
Humans
Language:
English
Journal:
Commun Biol
Year:
2021
Document Type:
Article
Affiliation country:
S42003-021-02441-2
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