Lipid nanoparticle (LNP)-mediated RNA delivery holds significant potential for the treatment of various liver diseases. Ionizable lipids play a crucial role in the formulation of LNPs and directly influence their delivery efficiency. In this study, we introduced an innovative concept by incorporating an ether bond into the hydrophobic tail of ionizable lipids for the first time. Three ionizable lipids, namely, ND-O1, ND-O2, and ND-O3, were synthesized based on 1-octylnonyl 8-[(2-hydroxyethyl)-[8-(nonyloxy)-8-oxooctyl] amino] octanoate (Lipid M). The efficacy of lipids-based LNPs for the delivery of the heat shock protein 47 (HSP47)-targeted siRNA to the liver was investigated. Compared to Lipid M-based LNP (LNP-M), it was observed that ND-O1 based LNP (LNP-O1) exhibited enhanced siRNA transfection efficiency in activated fibroblasts. In the fibrosis mice, LNP-O1 effectively suppressed HSP47 expression by approximately 84%, which was three times more effective than LNP-M, resulting in a significant decrease of collagen deposition and an amelioration of liver fibrosis. These findings highlighted the potential application of ND-O1 as an ionizable lipid for enhancing the efficient delivery of LNPs-delivered siRNA to the liver. Furthermore, this ionizable lipid design strategy offers a promising avenue for the improvement of the LNP delivery system.
