Rigid Shell Decorated Nanodevice with Fe/H₂O₂ Supply and Glutathione Depletion Capabilities for Potentiated Ferroptosis and Synergized Immunotherapy

Abstract The overexpressed glutathione peroxidase4 (GPX4) and insufficient H₂O₂ in tumor cells weaken ferroptosis therapy and the elicited anticancer immune response. Herein, a rigid metal‐polyphenol shell decorated nanodevice ssPPE_Lap@Fe‐TA is constructed to successfully overcome the drawbacks of ferroptosis therapy. The ssPPE_Lap@Fe‐TA consists of a rigid Fe‐TA network‐based shell and disulfide‐containing polyphosphoester (ssPPE) core with β‐lapachone loading. The rigid Fe‐TA network‐based shell of ssPPE_Lap@Fe‐TA enables its efficient internalization by tumor cell and then disintegrates in the acidic endosome/lysosome to initiate Fe³⁺/Fe²⁺ conversion‐driven ferroptosis. The ssPPE core will deplete glutathione (GSH) via the disulfide‐thiol exchange reaction to inactivate GPX4, and also trigger the release of β‐lapachone to significantly increase intracellular H₂O₂ and then promote Fe³⁺‐mediated Fenton reaction, eventually achieving strong inhibition of tumor progression. Moreover, ssPPE_Lap@Fe‐TA elicites a robust systemic antitumor immune response by promoting dendritic cells (DCs) maturation and T cell infiltration, and synergizes with anti‐PD‐L1 antibody (a‐PD‐L1) to strikingly suppress 4T1 tumor growth and lung metastasis.