Glucose Oxidase‐Powered Ferrium MOFs for Self‐Amplifying Fenton Catalysis and Photothermal Therapy

ABSTRACT Traditional metal‐organic frameworks (MOFs) suffer from limited responsiveness to the complex tumor microenvironment, systemic toxicity from non‐specific distribution, and compromised Fenton‐like efficiency due to antioxidants. To address these, we propose a multi‐modal synergistic strategy to functionalize MOFs and achieve chemodynamic and photothermal synergy without chemotherapeutics. A replacement MOFs system (FHMGA) integrated with hyaluronic acid, glucose oxidase, and gold nanoparticles is designed based on CD44 receptor recognition. In the acidic TME, FHMGA degrades and is reduced by overexpressed glutathione to Fe 2+ and Mn 2+ for further reaction with endogenous H 2 O 2 via Fenton‐like reactions to generate ·OH and induce oxidative stress. Under near‐infrared irradiation, gold nanoparticles exhibit high photothermal conversion efficiency, triggering local hyperthermia for thermal ablation. Simultaneously, heat enhances glucose oxidase‐powered catalysis, which catalyzes glucose oxidation in cancer cells to disrupt energy metabolism and produce additional H 2 O 2 , further boosting Fenton‐like reactions. Our results demonstrate that FHMGA exhibits significant anti‐tumor efficacy with minimal systemic toxicity. The triple synergy of oxidative damage from chemodynamic therapy, thermal ablation from photothermal therapy, and metabolic disruption via glucose oxidase significantly inhibits cancer cell growth by overcoming antioxidant‐mediated limitations. Self‐amplifying Fenton catalysis, while responsive degradation reduces systemic toxicity. This work advances precise cancer therapy by establishing a chemotherapy‐free, multi‐responsive synergistic system, addressing critical bottlenecks of ferrium‐based MOFs and providing a safer, more effective strategy for tumor‐specific treatment.