Small methodsJun 26, 2026

Changing the Tail Shape of Ionizable Lipids May Improve the Safety and Effectiveness of mRNA Delivery

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 27, 2026

Abstract

The resulting lipid nanoparticles exhibited encapsulation efficiencies higher than 90% and strong transfection potency.

Ionizable lipids with sterol-derived tails and branched dialkyl tails were designed to enhance mRNA delivery.
Lipid nanoparticles demonstrated favorable apparent pKa values ranging from 6.2 to 6.8.
The lead lipid nanoparticle (L1-aCho-e3 LNP) showed superior transfection efficiency compared to the benchmark SM-102 LNP.
Incorporation of additional cationic or anionic lipids altered the biodistribution of the nanoparticles.
mRNA@L1-aCho-e3 LNPs triggered robust antibody responses and provided full protection against lethal H1N1 challenge.

Simplified

Messenger RNA (mRNA) delivery critically depends on the molecular architecture of ionizable lipids within lipid nanoparticles (LNPs). We report a modular platform of sterol-containing ionizable lipids designed to probe how sterol motifs and branched dialkyl tails govern in vivo performance. Each lipid incorporates a sterol-derived (e.g., cholesterol) tail and a dialkyl tail with tunable branching and spatial arrangement, enabling systematic control over packing behavior, protonation characteristics, and nanoparticle assembly. The resulting LNPs exhibited favorable apparent pKa values (6.2-6.8), encapsulation efficiencies higher than 90%, and strong transfection potency. Our lead LNP (L1-aCho-e3 LNP) exhibited higher transfection efficiency than the benchmark SM-102 LNP. Incorporation of cationic (DOTAP) or anionic (DOPA) lipids as fifth components further demonstrated reorienting biodistribution from liver to lung or spleen. Finally, mRNA^H1N1@L1-aCho-e3 LNPs elicited robust antibody responses and full protection against lethal H1N1 challenge. These results reveal how rational sterol tail design can be applied to create ionizable lipids with tunable structural functional properties for next-generation mRNA therapeutics.

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Changing the Tail Shape of Ionizable Lipids May Improve the Safety and Effectiveness of mRNA Delivery

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