Lipid-392 is a hydrazide-linked ionizable lipid with three tertiary amines, three palmitoyl-containing branches and a hydroxyl-bearing C10 arm. It is the carrier lipid in an optimized, cholesterol-free simplified targeted lipid nanoparticle (stLNP) containing Lipid-392, POPE and DMG-PEG2000 at 90:8.5:1.5 mol%. In mice, this formulation produced 4.93-fold greater lung luciferase expression than DOTAP-5-LNP at 0.25 mg/kg intravenous mRNA dosing, with approximately 99% of the measured lung/liver/spleen expression signal in the lung. The study also demonstrated lung-cell Cre reporter activation, adenine base editing, siRNA-mediated gene silencing and IL-10 mRNA delivery in an acute lung injury model. These preclinical results support evaluation for pulmonary RNA delivery; activity depends on formulation, payload and experimental conditions.
