Design and synthesis of novel ionizable lipids enables highly efficient mRNA delivery via lipid nanoparticles

Lipid nanoparticles (LNPs) with alkane tails exhibited particle sizes mostly within 100-150 nm and encapsulation efficiencies exceeding 80%.

• LNPs displayed uniform distribution with a polydispersity index (PDI) less than 0.2.
• The apparent pKa of LNPs was influenced by both the headgroup's ability to gain protons and the size of the particles.
• Alkane-tailed LNPs demonstrated no significant toxicity to HepG2 cells at concentrations up to 200 μM, while some olefin-tailed LNPs were toxic at higher concentrations.
• In A549 cells, all LNPs inhibited cell proliferation, with the positive control DLin-MC3-DMA (MC3) showing reduced toxicity at elevated concentrations.
• Cellular uptake was notably high for small-sized LNPs, especially compounds 4 and 5, with compound 5 achieving a transfection efficiency of 67.80%, surpassing MC3's 53.16%.
• Compound 5 led to partial premature release of mRNA during endosomal acidification, contrasting with MC3's mechanism of cytoplasmic release.

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