Fe/Cu Bimetallic Metal-Organic Frameworks Nanoplatform: Efficient Chemodynamic Therapy via Multiway Amplification of Reactive Oxygen Species

Nanozyme-mediated tumor chemodynamic therapy (CDT) is severely hampered by insufficient nanozyme catalytic efficiency within weakly acidic and redox-imbalanced tumor microenvironments (TMEs) and unsatisfactory tumor-targeting accumulation. Herein, we rationally constructed a Fe/Cu bimetallic metal-organic framework (MOF) nanozyme carrier, which was loaded with 3-amino-1,2,4-triazole (3-AT) and surface-functionalized with folic acid, denoted MOF(Fe-Cu)@3-AT-FA (FCAF), for self-sustained and high-efficiency CDT. The nanoplatform simultaneously realized multiway ROS cascade amplification, involving folate-mediated active targeting, bimetallic electron transfer for strengthened intrinsic nanozyme activity, catalase inhibition by 3-AT to sustain sufficient H 2 O 2 substrates, and GSH exhaustion to attenuate intracellular antioxidant defense, serving as an all-in-one programmable nanoreactor. Benefiting from synergistic effects, FCAF achieved robust amplified CDT and remarkable oxidative stress damage. In vitro and in vivo results validated that FCAF markedly suppressed FRα-positive tumor proliferation with favorable biocompatibility. This study provided a universal cascade-amplification strategy for nanozyme-based CDT, laying novel perspectives for advanced nanotherapeutics.