ACS chemical biologyJul 16, 2026

Ionizable Silyl Lipids with Different Membrane Flexibility and mRNA Delivery Effects

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Jul 17, 2026

Abstract

Particles composed of single-chain silyl lipids can achieve higher encapsulation efficiency and distinct morphology compared to double-chain lipids.

Ionizable silyl-lipids with single or double alkyl chains were synthesized and evaluated for their effects on lipid nanoparticles.
Single-chain silyl lipids formed particles with more fluid membranes, while double-chain lipids created more rigid membranes.
Higher RNA encapsulation efficiency was observed in lipid nanoparticles made from single-chain silyl lipids.
Transfection efficiency varied based on lipid composition, with single-chain lipids demonstrating effectiveness even without helper lipids.
Phenyl-containing cationic silyl lipids may enhance mRNA transfection efficiency compared to standard controls.

Simplified

We report the synthesis and evaluation of ionizable silyl-lipids with single or double alkyl chains to modulate RNA encapsulation efficiency (EE), mRNA transfection, particle size, and membrane fluidity in lipid nanoparticles (LNPs). Incorporation of silyl lipid tails with varying tail substituents enables control over LNP properties, with distinct differences in membrane fluidity and transfection efficiency correlating with structure. Single-chain (MA) silyl lipids formed particles with more fluid membranes, while double-chain (DA) silyl lipids (similar to ALC-0315) formed particles with more rigid membranes, as determined using a C-Laurdan fluorescence assay. We show that particles composed of MA silyl lipids can have higher EE and distinct particle morphology (as determined using cryo-TEM) compared to DA lipids. The transfection efficiency was dependent on the particle composition, with MA lipids performing well even without the addition of helper lipids. Overall, this work highlights the potential of single- and double-chain ionizable silyl lipids to rationally modulate membrane fluidity and optimize LNP performance and demonstrates that phenyl-containing cationic silyl lipids can significantly enhance mRNA transfection efficiency relative to controls.

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Ionizable Silyl Lipids with Different Membrane Flexibility and mRNA Delivery Effects

Abstract

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