pH-regulating Lipiodol Pickering emulsions enhance transarterial embolization therapy via inducing ferroptosis and activating antitumor immunity

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.