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Ionization and structural properties of mRNA lipid nanoparticles influence expression in intramuscular and intravascular administration.
- Source :
-
Communications biology [Commun Biol] 2021 Aug 11; Vol. 4 (1), pp. 956. Date of Electronic Publication: 2021 Aug 11. - Publication Year :
- 2021
-
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.<br /> (© 2021. The Author(s).)
- Subjects :
- Administration, Intravenous
Animals
Drug Compounding
Humans
Hydrogen-Ion Concentration
Injections, Intramuscular
Mice
Molecular Structure
Nanoparticles ultrastructure
RNA, Messenger administration & dosage
RNA, Messenger pharmacokinetics
Spectrum Analysis
Tissue Distribution
Transfection
Gene Expression
Ions chemistry
Lipids chemistry
Nanoparticles chemistry
RNA, Messenger chemistry
RNA, Messenger genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2399-3642
- Volume :
- 4
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Communications biology
- Publication Type :
- Academic Journal
- Accession number :
- 34381159
- Full Text :
- https://doi.org/10.1038/s42003-021-02441-2