RRM2-targeted nanocarrier enhances radiofrequency ablation efficacy in hepatocellular carcinoma through ferroptosis amplification and immune remodeling

Hepatocellular carcinoma (HCC) is associated with high mortality rates despite the widespread application of radiofrequency ablation (RFA), which has limited therapeutic efficacy as a monotherapy. This study investigated ribonucleotide reductase M2 (RRM2) upregulation in post-RFA HCC tissues and developed a targeted nanoco-delivery system (red blood cell membrane/cRGD-modified pH-sensitive liposomes [sS@RBCM/cRGD-phLips]) to increase RFA efficacy through specific RRM2 knockout. RRM2 knockout synergistically amplified RFA-induced tumor cell death by promoting ferroptosis and immunogenic cell death. Mechanistically, RRM2 knockout upregulated the STAT1–IRF1–acyl-CoA synthetase long-chain family member 4 axis, which potentiated lipid peroxidation and ferroptosis. Furthermore, the nanocarrier system enhanced dendritic cell maturation and cytotoxic T cell infiltration, thereby remodeling the tumor immune microenvironment. In vivo experiments revealed that the combination of RFA- and RRM2-targeted nanoparticles significantly suppressed tumor growth and prolonged survival in HCC-bearing mice with minimal systemic toxicity. Notably, the dual-loaded nanoparticles also enhanced the efficacy of anti-programmed cell death protein 1 therapy, suggesting a promising combinatorial approach for HCC treatment. This study presents a novel therapeutic strategy that integrates RRM2-targeted gene editing with RFA, offering a robust and synergistic approach for improving HCC outcomes. The nanocarrier platform targets RRM2 in tumors and delivers iron oxide. Using a subcutaneous tumor model in C57BL/6J mice, the anti-tumor effects and mechanisms of the RRM2-targeted nanocarrier liver cancer were explored. Animal species: C57BL/6J mice; The experimental procedures included raising the mice, subcutaneously injecting LLC lung cancer cells, Hepal-6 liver cancer cells, and delivering drugs to the mice through a nano-carrier platform. After euthanasia, the tumor tissues were dissected.