Radiofrequency-responsive nanogel co-delivering cisplatin and EGCG for enhancing the efficacy of hepatocellular carcinoma interventional therapy by thermoresistance modulation and immune remodeling

A cisplatin/EGCG-loaded RF-responsive nanogel was developed for HCC interventional therapy. • Cisplatin amplifies RF deposition; EGCG inhibits HSP90-mediated thermotolerance, reducing residual tumors. • EGCG/CDDP@PNA induced ICD and remodeled TME via inhibiting the HSP90-STAT3-PD-L1 axis. Radiofrequency ablation (RFA) is a guideline-recommended first-line curative local treatment for hepatocellular carcinoma (HCC). Sublethal temperature zones at the tumor margin often lead to residual tumor survival, recurrence, and immune escape. To overcome these limitations, we developed a radiofrequency-responsive thermosensitive nanogel co-loading cisplatin and the HSP90 inhibitor epigallocatechin gallate (EGCG), termed EGCG/CDDP@PNA, which is administered via transcatheter arterial chemoembolization (TACE) followed by RFA to enhance ablation efficacy. The nanogel undergoes a body-temperature-triggered sol-gel transition, enabling tumor embolization and localized drug retention, and exhibits strong radiofrequency-responsive heating capability. Cisplatin increases intratumoral ionic conductivity, thereby amplifying radiofrequency energy deposition and accelerating intratumoral heating, while EGCG inhibits HSP90-mediated thermotolerance by disrupting the HSP90-STAT3-PD-L1 axis. In VX2 rabbit and Hepa1–6 orthotopic mouse hepatocellular carcinoma models, EGCG/CDDP@PNA significantly expanded the ablation zone, reduced sublethal residual tumor lesions, suppressed tumor progression, and prolonged survival. From the perspective of the tumor immune microenvironment, the nanogel induced immunogenic cell death, promoted dendritic cell activation and CD8 + T-cell infiltration, inhibited regulatory T cells, and remodeled the tumor immune microenvironment toward an immune-activated phenotype. Biosafety evaluations demonstrated good hemocompatibility and negligible systemic toxicity. Overall, EGCG/CDDP@PNA integrates physical energy modulation, molecular pathway inhibition, and immune microenvironment remodeling, providing a promising strategy to overcome thermotolerance and improve interventional treatment outcomes for HCC. Schematic Diagram of the Research. (A) Schematic diagram of EGCG/CDDP@PNA synthesis. (B) Investigation of the radiofrequency responsiveness of EGCG/CDDP@PNA in the VX2 rabbit orthotopic hepatocellular carcinoma model. (C) Investigation of the effect of EGCG/CDDP@PNA on immune activation in the C57BL/6 mouse orthotopic hepatocellular carcinoma model. Download: Download high-res image (157KB) Download: Download full-size image