Reprogramming hepatocellular carcinoma: Nanomedicine at the crossroads of molecular targets and smart delivery

Hepatocellular carcinoma (HCC) is a major health concern that comprises more than 80% of all liver cancer cases. The process of HCC tumorigenesis is complex with a multitude of factors contributing to its initiation and progression. Multiple signaling pathways are involved in HCC tumorigenesis, including PI3K/AKT, MEK/ERK, SDF-1/CXCR4, Wnt/β-catenin, Hippo, NF-κB, HIF-1α, and mitochondrial intrinsic apoptosis. This goes alongside the contributions of non-coding RNAs, as well as the dysregulation of anti-tumor immunity. The successful modulation of these signaling pathways holds a significant promise in providing effective treatments for HCC. Nanoparticles provide a potential platform for modulating these signaling pathways by regulating or inhibiting these pathways by including chemotherapeutic or genetic materials. Several examples include core-shell lipidic nanoparticles, lipidic nanocapsules, in addition to polymeric or metallic nanoparticles. The significance of nanoparticles lies in their ability to selectively deliver small molecules, genetic material, and antibodies to the intended site of action with adequate protection and enhanced efficiency. In addition to nanoparticles, multiple advanced approaches exist, including micro/nanobubbles, exosomes, and mesenchymal stem cells. This review aims to unveil the significant potential of nanoparticles to modulate multiple critical molecular pathways in HCC tumorigenesis by delivering diverse types of active ingredients. This review also provides a brief overview of emerging advanced drug delivery systems beyond nanoparticles, highlighting their promise in modulating HCC signaling pathways.