Hepatocellular carcinoma (HCC) remains a leading driver of cancer-related mortality, characterized by profound heterogeneity and a formidable Tumor microenvironment (TME). Conventional therapeutic interventions, including traditional chemotherapy and targeted small molecules, are frequently hindered by critical limitations such as poor aqueous solubility, rapid metabolic clearance, severe systemic toxicity, and the rapid onset of multidrug resistance. Furthermore, these free therapeutic agents struggle to penetrate the dense hepatic stroma. Nanoscale drug delivery systems (NDDS) have emerged as a transformative paradigm to overcome these intractable bottlenecks. By leveraging size-mediated passive accumulation, active ligand recognition, and intelligent microenvironment-responsive designs, nanocarriers can significantly prolong systemic circulation, facilitate deep tumor penetration, and achieve spatiotemporally controlled payload release. This review provides a comprehensive and critical analysis of the evolving landscape of HCC nanomedicine. We systematically evaluate the delivery mechanisms and pharmacokinetics of phytochemicals, synthetic molecules, and advanced gene therapeutic modules (RNAi and CRISPR/Cas9). Furthermore, we provide a comparative evaluation of sustainable “green” biomaterials against traditional carriers, detail sophisticated surface functionalization strategies that range from ranging from ligand-mediated targeting to cell-membrane biomimetic “stealth” coatings and explore multi-stimuli responsive platforms. Finally, we critically discuss current clinical translational bottlenecks, including protein corona formation, immunogenicity, and scalable manufacturing, thereby offering a strategic roadmap for the clinical realization of next-generation hepatic nanotherapeutics. The diagram sequentially outlines the critical transition from traditional therapy limitations, including poor bioavailability and systemic toxicity, to advanced nanocarrier encapsulation. It demonstrates how precise homing and active targeting facilitate selective accumulation in pathological tissues. Furthermore, the illustration highlights stimuli responsive platforms that achieve controlled payload release via specific microenvironmental triggers such as pH and enzymes. This coordinated therapeutic cascade ultimately drives enhanced efficacy and successful tumor regression while preserving healthy cells
Fu et al. (Fri,) studied this question.