【Title】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 (H₂O₂) and high expression of glutathione (GSH) in tumor cells restrict the efficiency of iron-based nanocarriers in inducing ferroptosis. Herein, we reported a ferric phosphate nanotherapeutic system (denoted as FeP@HCPT-HA) with H₂O₂-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, Fe²⁺ and Fe³⁺. As a chemotherapy drug, HCPT not only induces tumor cell apoptosis but also supplies H₂O₂ for Fe²⁺-mediated Fenton reaction to enhance ferroptosis. The released Fe³⁺ depletes GSH by the redox reaction between Fe³⁺ 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 H₂O₂-supply and GSH-elimination, endow the FeP@HCPT-HA with effective tumor growth inhibition by the enhanced ferroptosis and chemotherapy.

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