Lipid-based Nanomedicine for Hepatocellular Carcinoma: Flavonoid-Enhanced, Pathway-Specific Sirna Delivery Strategies and Clinical Progress

Hepatocellular carcinoma (HCC) is still one of the most morbid cancers in the world, mainly due to delayed diagnosis resulting from significant molecular heterogeneity and rapid acquisition of resistance to treatment. Definitive therapies such as surgery and locoregional techniques have been successful in a subset of patients, yet systemic chemotherapy and overall FDA-approved targeted agents offer only modest improvement for advanced disease. siRNA-based therapy provides a targeted silencing mechanism for the selective downregulation of oncogenic drivers and resistance-associated pathways. However, the clinical translation of siRNA therapeutics is critically contingent upon safe and effective delivery platforms that are clinically viable. Lipid-based nanomedicines are thus far among the most effective carriers for siRNA delivery because of their excellent biocompatibility, natural affinity with the liver, easy scalable production and clinical feasibility. This review provides critical insight into major molecular pathways involved in HCC development, such as angiogenic signaling, growth factor cascades and survival and metabolic networks, which offer potential targets for pathway-specific siRNA intervention. The physicochemical characteristics, delivery strategies, formulation techniques, mechanisms of endosomal escape and fine-tuning of the transfection efficiency of lipid-based siRNA carriers are comprehensively reviewed. In addition, prominent preclinical lipid-based nanotechnologies designed to target major oncogenes and survival mediators are outlined in conjunction with translation implications, including production cost, scalability, and regulatory readiness. The current status of the clinical development of lipid-based siRNA therapeutics for HCC is also discussed, with a focus on safety and the constraints associated with monotherapy. The role that artificial intelligence plays in siRNA sequence optimization, biodistribution prediction and formulation development is also described. Finally, challenges and perspectives are discussed, including multipathway silencing tactics, linkages with immunotherapy, and personalized nanomedicine to increase therapeutic effectiveness in HCC.