Rigid Shell Decorated Nanodevice with Fe/H<sub>2</sub>O<sub>2</sub> Supply and Glutathione Depletion Capabilities for Potentiated Ferroptosis and Synergized Immunotherapy
Xu Dai, Yueqiang Zhu, Miao Su, Junbin Chen, Song Shen, Cong‐Fei Xu, Xianzhu Yang
Abstract
Abstract The overexpressed glutathione peroxidase4 (GPX4) and insufficient H 2 O 2 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 Fe 3+ /Fe 2+ 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 H 2 O 2 and then promote Fe 3+ ‐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.