S-Ac7-DOg is an ionizable lipid engineered for optimized mRNA delivery to the retina, featuring a sulfur-based ester bond (S-Ac) and dual oleyl glyceride chains (DOg). Its pKa (~6.74) is finely tuned to enhance endosomal escape in acidic environments, enabling efficient cytosolic mRNA release. Unlike traditional lipids (e.g., C12-200, MC3), S-Ac7-DOg incorporates biodegradable ester linkages that hydrolyze intracellularly, minimizing lipid accumulation and reducing innate immune activation.
In vitro, S-Ac7-DOg LNPs achieved >80% transfection efficiency in retinal cells (ARPE-19, MIO-M1) with negligible cytokine secretion, outperforming MC3 and rivaling C12-200 while avoiding the latter’s high immunogenicity. In vivo, intravitreal delivery in mice showed robust protein expression in the optic nerve head (ONH) and Müller glia (75–100% of eyes), sustained for ≥7 days. Critically, it induced the lowest immunogenicity among tested lipids: minimal leukocyte infiltration (<1.5-fold vs. PBS), no microglial reactivity, and reduced GFAP upregulation.
