Biodegradable Ferric Phosphate Nanocarriers with Tumor‐Specific Activation and Glutathione Depletion for Tumor Self‐Enhanced Ferroptosis and Chemotherapy

Abstract Ferroptosis is a regulatory cell death that is dependent on iron‐mediated lipid peroxidation and cell membrane damage. The use of iron‐based nanocarriers to activate ferroptosis is of great significance in oncotherapy. However, the limited endogenous hydrogen peroxide (H 2 O 2 ) and high expression of glutathione (GSH) in tumor cells restrict the efficiency of iron‐based nanocarriers in inducing ferroptosis. Herein, a ferric phosphate nanotherapeutic system (denoted as FeP@HCPT‐HA) is reported with H 2 O 2 ‐supply and GSH‐elimination properties for tumor self‐enhanced ferroptosis and chemotherapy. FeP@HCPT‐HA is obtained by a coprecipitation method with the in situ loading of 10‐hydroxycamptothecin (HCPT), followed by the modification of hyaluronic acid (HA). FeP@HCPT‐HA actively targets CD44‐overexpressed tumor cells and degrades in acidic tumor microenvironment to release HCPT, Fe 2+ and Fe 3+ . As a chemotherapy drug, HCPT not only induces tumor cell apoptosis but also supplies H 2 O 2 for Fe 2+ ‐mediated Fenton reaction to enhance ferroptosis. The released Fe 3+ depletes GSH by the redox reaction between Fe 3+ and GSH, which down‐regulates the expression of glutathione peroxidase 4 (GPX4) and enhances lipid peroxidation, resulting in enhanced ferroptosis. The integration of tumor targeting and tumor‐specific activation, as well as H 2 O 2 ‐supply and GSH‐elimination, endow the FeP@HCPT‐HA with effective tumor growth inhibition by the enhanced ferroptosis and chemotherapy.