Drug Delivery Systems for Hepatocellular Carcinoma: Bridging Pathophysiological Barriers and Advanced Nanomedicine Strategies.

Hepatocellular carcinoma (HCC) is characterized by high heterogeneity, a complex tumor microenvironment, and multiple physiological barriers that limit conventional therapies and cause significant toxicity. Drug delivery systems (DDS), particularly nanoscale delivery systems, offer promising opportunities to overcome these obstacles through passive targeting, active targeting, and stimuli-responsive drug release. Nevertheless, despite substantial progress in preclinical research, the clinical translation of most DDS remains challenging. This review systematically outlines the pathophysiological rationale underpinning DDS design for HCC, including the aberrant vasculature, hypoxia, low pH, overexpressed enzymes and immunosuppressive features of the TME, as well as liver-specific barriers. Subsequently, we comprehensively evaluate the progress and limitations of passive targeting, active targeting, stimuli-responsive, and locoregional delivery systems. Furthermore, we dissect the core bottlenecks currently impeding clinical translation: tumor heterogeneity, the "interlocking chain" effect of multiple biological barriers, uncertainty of the EPR effect, multidrug resistance mechanisms, poorly defined long-term safety of nanocarriers, and the "valley of death" caused by discrepancies between preclinical models and human disease. Finally, we envision future directions: next-generation targeting strategies should focus on CSCs and metastasis; DDS must be deeply integrated with immunotherapy to remodel the immune microenvironment; biomimetic and bio-derived delivery systems may circumvent inherent limitations of synthetic carriers; multifunctional theranostic platforms enable real-time monitoring and personalized treatment; and establishing more clinically relevant animal models alongside personalized DDS design paradigms is key to accelerating translation. Our central argument is that the future success of DDS for HCC will no longer rely on the "showmanship" of individual technologies, but rather on a "systems engineering" approach grounded in a profound understanding of HCC biological heterogeneity, with the core objectives being precise spatiotemporal control of drug distribution and beneficial interactions with the host immune system.