Abstract

Transcatheter arterial chemoembolization (TACE) faces limitations in hepatocellular carcinoma (HCC) due to suboptimal drug pharmacokinetics and immunosuppression post-embolization. This study develops iron nanoparticles (FeNPs) with pH-responsive Fenton activity as surfactants for a Lipiodol Pickering emulsion (LPE) to deliver cariporide, targeting tumor acidity. Cariporide inhibits plasma membrane sodium-hydrogen exchangers, reducing intracellular pH to amplify FeNP-induced ferroptosis while suppressing extracellular acidosis by blocking proton extrusion. The cariporide-loaded FeNP-LPE (CFe-LPE) promotes immunogenic cell death and reverses immunosuppressive tumor microenvironments by alleviating acidity. In multiple orthotopic HCC models, CFe-LPE-based transarterial embolization outperforms conventional doxorubicin-Lipiodol TACE, demonstrating that dual modulation of intra/extracellular pH enhances Fenton-catalytic embolic agents by synergistically activating antitumor immunity.