A Biomimetic Cell Membrane-Coated Nanoreactor Reshapes ROS Homeostasis and Activates STING Pathway for Synergistic Chemodynamic–Immunotherapy

The combination of chemodynamic therapy (CDT) and immunotherapy offers a promising therapeutic paradigm for advanced cancer treatment, yet its translation is largely hindered by inadequate intratumoral reactive oxygen species (ROS) production and the lack of a robust link between ROS-induced cytotoxicity and durable immune activation. To address these challenges, we herein engineer a multifunctional biomimetic nanoplatform (ZMGM) by encapsulating Mn2+ and glucose oxidase (GOX) within zeolitic imidazolate framework-8 (ZIF-8), followed by surface functionalization with 4T1 breast cancer cell membranes. This design integrates three synergistic functions: (1) GOX depletes glucose and generates hydrogen peroxide (H2O2) within the acidic tumor microenvironment; (2) the produced H2O2 fuels the Mn2+-mediated Fenton-like reaction to amplify ROS production; and (3) Mn2+ simultaneously serves as a potent stimulator of interferon genes (STING) agonist, triggering type-I interferon responses and promoting dendritic cell maturation. Meanwhile, the homologous cancer cell membrane coating endows ZMGM with specific tumor homing and enhanced tumor localization. Both in vitro and in vivo findings demonstrate that ZMGM not only efficiently eradicates primary tumors but also induces a systemic antitumor immune response, characterized by increased CD8+ T cell infiltration, that effectively suppresses distant metastatic lesions. Notably, the synergistic CDT-STING immunotherapy achieves a primary tumor inhibition rate of 84.22% without obvious systemic toxicity. This work provides a paradigm for rationally designing a single nanoplatform that bridges ROS-mediated cell killing and innate immune activation, offering a promising avenue for combating metastatic triple-negative breast cancer.