Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, with systemic therapies offering only limited benefit. Sorafenib, the first-line multi-kinase inhibitor, is constrained by poor pharmacokinetics, dose-limiting toxicities, and the rapid emergence of resistance. Nanotechnology-based drug delivery systems (NDDS) provide promising strategies to address these limitations. This review summarizes recent NDDS innovations that enhance sorafenib’s therapeutic efficacy in HCC. Major nanocarrier classes, including lipid-based, polymeric, inorganic, and biogenic platforms, are discussed together with modifications for passive or active tumor targeting, such as asialoglycoprotein receptor-mediated approaches. Special attention is given to stimuli-responsive systems that exploit tumor microenvironmental cues to achieve localized drug release. Co-delivery strategies that combine sorafenib with chemotherapeutics, RNA interference agents, or immune modulators are also highlighted for their capacity to amplify antitumor activity and overcome resistance. Artificial intelligence (AI) is emerging as a tool to support the rational design and personalization of nanomedicines. While encouraging preclinical evidence demonstrates improved pharmacokinetics, tumor accumulation, and efficacy, challenges in scalable production, biosafety, and regulatory approval remain. Collectively, these developments emphasize the potential of sorafenib nanomedicines while underscoring the need to resolve key barriers for clinical translation.

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, with systemic therapies offering only limited benefit. Sorafenib, the first-line multi-kinase inhibitor, is constrained by poor pharmacokinetics, dose-limiting toxicities, and the rapid emergence of resistance. Nanotechnology-based drug delivery systems (NDDS) provide promising strategies to address these limitations. This review summarizes recent NDDS innovations that enhance sorafenib’s therapeutic efficacy in HCC. Major nanocarrier classes, including lipid-based, polymeric, inorganic, and biogenic platforms, are discussed together with modifications for passive or active tumor targeting, such as asialoglycoprotein receptor-mediated approaches. Special attention is given to stimuli-responsive systems that exploit tumor microenvironmental cues to achieve localized drug release. Co-delivery strategies that combine sorafenib with chemotherapeutics, RNA interference agents, or immune modulators are also highlighted for their capacity to amplify antitumor activity and overcome resistance. Artificial intelligence (AI) is emerging as a tool to support the rational design and personalization of nanomedicines. While encouraging preclinical evidence demonstrates improved pharmacokinetics, tumor accumulation, and efficacy, challenges in scalable production, biosafety, and regulatory approval remain. Collectively, these developments emphasize the potential of sorafenib nanomedicines while underscoring the need to resolve key barriers for clinical translation.