Introduction: Hepatocellularcarcinoma (HCC), the primary form of liver cancer, is the second leading cause of cancer-related deaths worldwide. Current therapies have limited effectiveness, particularly in advanced stages of the disease, highlighting the need for innovative treatment options. Small-interfering RNA(siRNA) molecules show great promise as a therapeutic solution since they can inhibit the expression of genes promoting HCC growth. Their cost-effective synthesis has further encouraged their potential use as novel drugs. However, siRNAs are vulnerable to degradation in biological environments, necessitating protective delivery systems. Additionally, targeted delivery to HCC is critical for optimal efficacy and minimal undesired side effects. Areacovered: This review addresses the challenges associated with the delivery of siRNA toHCC, discussing and focusing on delivery systems based on lipid and polymeric nanoparticles in publications from the past five years. Expert opinion: Future nano particles will need to effectively cross the vessel wall, migrate through the extracellular matrix and finally cross the HCC cell membrane. This may be achieved by optimizing nanoparticle size, the equipment of nanoparticles withHCC targeting moieties and loading nanoparticles with siRNAs againstHCC-specific oncogenes.
