Ionizable Lipid Nanoparticles for Targeted Delivery of siRNA

Abstract

Ionizable lipid nanoparticles (LNP)-mediated siRNA delivery provides a promising technological platform for cancer gene therapy. Traditional cancer treatment methods primarily focus on directly killing tumor cells, but RNA interference-based siRNA therapy can regulate the expression of genes related to disease, representing a therapeutic strategy shifting from "killing tumors" to "regulating genes." LNP, as one of the most mature non-viral nucleic acid delivery systems currently available, relies on its adjustable lipid composition, good biosafety and pH-responsive charge-conversion capability, and is able to protect siRNA from acid-enzyme degradation, promote cellular uptake, and achieve endosomal escape. Therefore, it overcomes key delivery barriers, such as the poor in vivo stability and low cellular uptake efficiency of naked siRNA. The successful approval of Onpattro fully verified the possibility of clinical translation of the LNP-siRNA delivery platform. However, the current LNP system still has issues, such as insufficient tumor targeting, accumulation in non-target tissues, and difficulty in precisely regulating them in vivo behavior. To overcome the above bottlenecks, researchers have been continuously improving the active tumour-targeting ability and delivery precision of LNPs through methods such as surface functionalization and modification of lipid composition. First, the composition and structure of ionizable LNPs and their targeted delivery mechanism are introduced in this review. then, various targeted modification strategies for tumor siRNA delivery are systematically listed, including peptides, antibodies, amino acids, and receptor-ligand systems, and finally, the current challenges and future directions are summarized.