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

## TL;DR

A new pH-responsive emulsion improves liver cancer treatment by reducing tumor acidity and boosting the immune response.

## Contribution

A pH-regulating Lipiodol Pickering emulsion is developed to enhance embolization therapy through ferroptosis and antitumor immunity.

## Key findings

- CFe-LPE outperforms doxorubicin-Lipiodol TACE in orthotopic HCC models.
- Cariporide reduces intracellular and extracellular acidity by blocking proton extrusion.
- The system induces immunogenic ferroptosis and reverses tumor immunosuppression.

## 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.

•FeNP-stabilized Lipiodol Pickering emulsion enables pH-responsive cariporide delivery•Cariporide reduces intracellular pH and extracellular acidosis via blocking H+ efflux•Cariporide synergizes with FeNPs to induce ferroptosis and antitumor immunity•Dual modulation of intra/extracellular pH enhances Fenton-catalytic embolic agents

FeNP-stabilized Lipiodol Pickering emulsion enables pH-responsive cariporide delivery

Cariporide reduces intracellular pH and extracellular acidosis via blocking H+ efflux

Cariporide synergizes with FeNPs to induce ferroptosis and antitumor immunity

Dual modulation of intra/extracellular pH enhances Fenton-catalytic embolic agents

Yang et al. develop an iron nanoparticle-stabilized Lipiodol Pickering emulsion that enables sustained delivery of cariporide, which concurrently modulates extracellular and intracellular acidity by inhibiting sodium-hydrogen exchangers. This embolic system enhances transarterial embolization by inducing immunogenic ferroptosis and reversing tumor immunosuppression from acidity, outperforming doxorubicin-Lipiodol chemoembolization.