Ionizable Lipid Nanoparticles as a siRNA Delivery Carrier: A Review

Abstract

Abstract Small interfering RNA (siRNA)-based gene silencing has evolved as a promising strategy for treating a wide range of human diseases. However, naked siRNA molecules are susceptible to degradation by cellular nucleases, immune activation, and rapid renal clearance. Therefore, various siRNA delivery vectors have been developed, among which lipid nanoparticles (LNPs) have received significant attention due to their excellent biocompatibility and low immunogenicity. Conventionally, permanent cationic lipids were used for the fabrication of LNPs, but their clinical translation was limited by cytotoxicity, immunogenicity, and non-specific interactions. To overcome these limitations, significant progress has been made in developing advanced LNPs using ionizable lipids (ILs) (termed as IL nanoparticles or iLNPs) that are neutral at physiological pH but acquire a positive charge in the acidic endosomal compartments, thereby minimizing toxicity and facilitating efficient endosomal escape. This review summarizes the different vectors for siRNA delivery, the evolution of iLNPs, their composition, and surface modification strategies. Furthermore, we discuss the application of iLNP-mediated siRNA therapy for several human diseases, including an FDA-approved therapy. Finally, we highlight the current challenges of iLNP-based siRNA therapeutics and possible artificial intelligence-guided approaches for the rational design and development of next-generation iLNPs for effective siRNA delivery.