Advances in Lipid-Based Nanomedicine: Pathway Specific siRNA Therapy and Optimizing Delivery for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a major global health issue, ranking as the sixth most common cancer and a leading cause of cancer-related deaths worldwide. Risk factors for HCC include chronic hepatitis B and C, obesity, alcohol abuse, diabetes, and metabolic disorders. Current treatments, such as surgery, transplantation, and chemotherapy, are often ineffective in advanced stages due to tumor resistance and the inability to target key oncogenic pathways. Recent advances in small interfering RNA (siRNA) therapy offer a promising solution to silence these pathways and hinder tumor progression. Nanoparticles, especially lipid-based nanoparticles (LNPs) like liposomes, solid lipid nanoparticles, exosomes etc. have emerged as an effective platform for siRNA delivery. LNPs provide critical advantages, including protection of siRNA from enzymatic degradation, improved cellular uptake, and precise tumor targeting through functionalization strategies. Compared to polymeric and metallic nanocarriers, LNPs demonstrate superior biocompatibility, biodegradability, and safety profiles. Furthermore, their ability to exploit natural mechanisms, such as apolipoprotein E (ApoE)-mediated uptake via low-density lipoprotein receptors on hepatocytes, enhances liver-specific delivery. This review explores advancements in siRNA therapeutics for HCC, highlighting nanoparticle-based delivery, cell signaling targets, and synthesis strategies. It also examines AI's role in optimizing siRNA design, formulation, and personalized treatment. These innovations enhance pathway-specific therapies, advancing clinical translation and improving HCC outcomes.