Targeted delivery systems of siRNA based on ionizable lipid nanoparticles and cationic polymer vectors

As an emerging therapeutic tool, small interfering RNA (siRNA) had the capability to down-regulate nearly all human mRNAs via sequence-specific gene silencing. Numerous studies have demonstrated the substantial potential of siRNA in the treatment of broad classes of diseases. With the discovery and development of various delivery systems and chemical modifications, six siRNA-based drugs have been approved by 2024. The utilization of siRNA-based therapeutics has significantly propelled efforts to combat a wide array of previously incurable diseases and advanced at a rapid pace, particularly with the help of potent targeted delivery systems. Despite encountering several extracellular and intracellular challenges, the efficiency of siRNA delivery has been gradually enhanced. Currently, targeted strategies aimed at improving potency and reducing toxicity played a crucial role in the druggability of siRNA. This review focused on recent advancements on ionizable lipid nanoparticles (LNPs) and cationic polymer (CP) vectors applied for targeted siRNA delivery. Based on various types of targeted modifications, we primarily described delivery systems modified with receptor ligands, peptides, antibodies, aptamers and amino acids. Finally, we discussed the challenges and opportunities associated with siRNA delivery systems based on ionizable LNPs and CPs vectors.