Hypoxia-augmented and photothermally-enhanced ferroptotic therapy with high specificity and efficiency

The rigorous reaction conditions (sufficient H₂O₂ and a low pH value) of an efficient Fenton reaction limit its further biomedical translation. Therefore, it is urgent to improve the efficacy of the Fenton reaction at the tumor site for efficient ferroptotic therapy. Herein, a hypoxia-responsive-Azo-BSA functionalized biomimetic nanoreactor (Fe(iii)-GA/GOx@ZIF-Azo), encapsulating ultrasmall ferric-gallic acid coordination polymer nanoparticles (Fe(iii)-GA) and glucose oxidase (GOx) into a zeolitic imidazolate framework (ZIF), was constructed for tumor ablation through an intensive Fenton reaction accelerated by not only sustained Fe²⁺ and H₂O₂ supply but also low pH and photothermal stimulation. Moreover, Azo achieved charge reversal in a hypoxia microenvironment caused by the sustained oxygen consumption by GOx, which resulted in selective and enhanced tumor accumulation based on the hypoxia-activated positive feedback cellular uptake. This rationally designed biomimetic nanoreactor might lay a foundation for the clinical translation of ferroptotic therapy.