Polymeric Nanomedicines for siRNA Delivery in Hepatocellular Carcinoma: Emerging Therapeutic Strategies, Combination Approaches, and Translational Perspectives

Hepatocellular carcinoma is the sixth most common cancer worldwide and a leading cause of cancer related mortality. Risk factors include chronic hepatitis B/C, obesity, alcohol abuse, diabetes and metabolic disorders. In advanced stages, normal treatments such as surgery, transplantation and chemotherapy are not as effective as tumors develop resistance and do not target oncogenic pathways well. Small interfering RNA (siRNA) therapeutics have the potential to change treatment paradigms by silencing specific biological pathways, thus suppressing tumor progression. Polymeric nanoparticles (PNPs) such as poly(lactic-co-glycolic acid) (PLGA), polyethyleneimine (PEI) and stimuli-responsive copolymers have attracted attention as effective delivery systems for siRNA. These carriers protect siRNA from enzymatic degradation and facilitate its cellular uptake. Furthermore, the surface of the carriers can be modified with targeting ligands, eg, galactose or ASGPR antibodies, to improve tumor-specific delivery. The PNPs can be tuned to change their physical and chemical properties, are more stable and responsive to signals from the tumor microenvironment for regulated release. This means they perform better than lipophilic or metallic carriers. Hepatocyte specific absorption pathways even enhance the liver tropism. This review focuses on recent advances in siRNA based therapeutic strategies against hepatocellular carcinoma, with a special focus on PNPs mediated drug delivery systems. It describes significant oncogenic pathways like β-catenin and STAT3 and formulation techniques including nanoprecipitation and layer by layer assembly. The review also reports the increasing importance of artificial intelligence in siRNA design, formulation optimization, and personalized therapeutic methods to improve the clinical applicability of HCC treatment.