A multifunctional bimetallic MOF nanozyme orchestrating ferroptosis-apoptosis synergy for enhanced gastric tumor immunotherapy.

Nanozymes have revolutionized tumor therapy due to their distinctive enzyme-like catalytic properties. However, traditional nanozymes often face limitations, including inadequate targeting capabilities, limited catalytic efficiency, and low therapeutic efficacy of single-pathway mechanisms. Herein, we successfully developed a bimetallic MOF-based nanozyme loaded with 5-fluorouracil and decorated with aPD-L1. This novel nanozyme platform-designated as 5-FUZIF-8@FeaPD-L1-effectively regulated oxygen release, hydroxyl radical generation, and glutathione depletion through multi-enzyme-like catalytic activities, which alleviated hypoxia and induced apoptosis and ferroptosis in the tumor cells. Density functional theory calculations confirmed enhanced peroxidase-/catalase-like activity and glutathione depletion capacity of the nanozyme. Furthermore, 5-FUZIF-8@FeaPD-L1 demonstrated effective tumor targeting and biosafety, and disintegrated rapidly in the acidic tumor microenvironment to release 5-FU, aPD-L1, and Fe2+, which synergistically induced apoptosis and ferroptosis in the tumor cells. The dual cytotoxic effects synergized with aPD-L1 to reverse immunosuppression by promoting the polarization of tumor-associated macrophages to the M1-like phenotype, enhancing CD8+ T cell infiltration, and facilitating cytokine secretion. In summary, a nanozyme based on bimetallic MOFs achieved significant anti-tumor activity through synergistic ferroptosis, apoptosis, and immunotherapy. The findings of this study broaden the application potential of bimetallic MOF nanozymes and provide new insights for the development of novel anti-tumor therapeutic strategies.