• The novel drug delivery system significantly enhances the antitumor efficacy of sorafenib in hepatocellular carcinoma.
• The combination therapy reduces systemic toxicity compared to free sorafenib, improving the therapeutic index.
• Mechanistic studies reveal increased apoptosis and inhibition of angiogenesis as key drivers of the enhanced efficacy.
• This preclinical evidence supports the translation of the sorafenib-loaded DDS into clinical trials for HCC treatment.