Synergistic Chemoimmunotherapy of Hepatocellular Carcinoma via ROS-Responsive Carrier-Free Prodrug Nanoparticles

Carrier-free nanomedicines, with their high drug-loading capacity and low carrier-associated toxicity, offer a promising strategy for synergistic cancer therapy. Here, we developed a reactive oxygen species (ROS)-responsive, carrier-free nanoparticle (PRO/OCA NP) self-assembled from a resveratrol prodrug (PRO) and the immune adjuvant obeticholic acid (OCA). The oxalate ester linkage enabled selective cleavage in the ROS-enriched tumor microenvironment, ensuring precise co-release of Res and OCA. This dual delivery suppressed hepatocellular carcinoma (HCC) proliferation, induced apoptosis and cell cycle arrest, and inhibited PI3K/AKT/mTOR signaling. Meanwhile, PRO/OCA NPs trigger immunogenic cell death in tumor cells, activating NK and NKT cells and enhancing their cytotoxic functions, thereby amplifying the innate immune responses. In an orthotopic HCC mouse model, PRO/OCA markedly inhibited both primary and metastatic tumors while exhibiting favorable biocompatibility. Compared with monotherapy or simple drug combinations, this platform achieves a "1 + 1 > 2" chemo-immunotherapeutic synergy, offering a strategy with translational potential for comprehensive HCC treatment.