Calcification-Mediated Dual-Starvation and Immune Activation for Transarterial Chemoembolization.

INTRODUCTION: Transarterial chemoembolization (TACE) remains a cornerstone therapy for hepatocellular carcinoma (HCC), but its efficacy is frequently limited by inadequate drug penetration and tumor dissemination. METHODS: We developed a thermosensitive PND nanogel co-encapsulating tirapazamine (TPZ) and folic acid (FA), TPZ/FA@PND. The system was evaluated for sustained drug release, physiological temperature-triggered sol-gel transition, in vitro antitumor effects under normoxia and hypoxia, calcification induction, biocompatibility, and in vivo therapeutic efficacy in a VX2 tumor-bearing rabbit TACE model. RESULTS: TPZ/FA@PND showed sustained release and physiological temperature-triggered gelation. In vitro, TPZ/FA@PND inhibited tumor cell proliferation, migration, and invasion under hypoxia while inducing extracellular calcification, with negligible hemolysis and minimal hepatotoxicity. In vivo, TPZ/FA@PND delivered via TACE achieved complete embolization, induced marginal calcification, reduced metastasis, inhibited VEGF and MMP-9 expression, enhanced CD8+ T-cell infiltration, and promoted systemic antitumor immunity. DISCUSSION: This dual-starvation nanogel strategy integrates embolization, calcification-mediated containment, and immune activation, offering a clinically translatable approach to improve the therapeutic efficacy and long-term outcomes of TACE for HCC.