High-throughput synthesis and optimization of ionizable lipids through A³ coupling for efficient mRNA delivery.

ABSTRACT:

Background

The efficacy of mRNA-based vaccines and therapies relies on lipid nanoparticles (LNPs) as carriers to deliver mRNA into cells. The chemical structure of ionizable lipids (ILs) within LNPs is crucial in determining their delivery efficiency.

Results

In this study, we synthesized 623 alkyne-bearing ionizable lipids using the A³ coupling reaction and assessed their effectiveness in mRNA delivery. ILs with specific structural features-18-carbon alkyl chains, a cis-double bond, and ethanolamine head groups-demonstrated superior mRNA delivery capabilities. Variations in saturation, double bond placement, and chain length correlated with decreased efficacy. Alkynes positioned adjacent to nitrogen atoms in ILs reduced the acid dissociation constant (pKa) of LNP

SUBMITTER: Li J 

PROVIDER: S-EPMC11536852 | biostudies-literature | 2024 Nov

REPOSITORIES: biostudies-literature