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

作者：Dai, Xu; Zhu, Yueqiang; Su, Miao; Chen, Junbin; Shen, Song; Xu, Cong-Fei; Yang, Xianzhu^*

来源：Advanced Functional Materials, 2023, 33(27).

DOI：10.1002/adfm.202215022

• cell membrane interactions
• Fe3+
• H2O2 supply
• ferroptosis
• glutathione depletion
• immunotherapy
• rigid Fe3+-TA shell

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 beta-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 beta-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.