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Abstract
A total of 623 alkyne-bearing were synthesized and assessed for mRNA delivery efficiency.
- Ionizable lipids with 18-carbon alkyl chains, a cis-double bond, and ethanolamine head groups showed superior mRNA delivery capabilities.
- Changes in the saturation, double bond placement, and chain length of ionizable lipids were linked to decreased mRNA delivery efficacy.
- Alkynes located next to nitrogen atoms in ionizable lipids reduced the acid dissociation constant (pKa) of lipid nanoparticles, hindering mRNA delivery efficiency.
- Transforming alkynes into alkanes significantly improved mRNA delivery both in laboratory settings and in living organisms.
- Optimized ionizable lipids combined with cKK-E12 produced lipid nanoparticles that enhanced mRNA expression levels in living organisms.
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