Ionizable lipid chemistry in lipid nanoparticles determines delivery efficiency to hepatic stellate cells

Systemic administration of 0.3 mg/kg body weight siRNA cocktails resulted in 0-80% Reln suppression across 12 ionizable lipids.

• Ionizable lipid chemistry influences the efficiency of delivering LNPs to hepatic stellate cells (HSCs).
• The ALC-0315 LNP demonstrated dose-dependent activity in HSCs, with an effective dose of approximately 0.03 mg/kg body weight.
• Durable silencing of target genes was achieved, with suppression lasting up to 88% over two weeks without observed toxicity at 2 mg/kg.
• Delivery efficiency to HSCs may be affected by the dipole moment of the ionizable lipids.
• In primary human activated HSCs, ALC-0315 LNPs showed greater cellular uptake and effective knockdown of heat shock protein 47 compared to MC3 LNPs.

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