A Self-Cascade Nanozyme of Metformin-Stabilized Amorphous Iron Oxide With Ultrahigh Fe(II) for Potent Tumor Therapy...

The therapeutic efficacy of iron oxide nanozymes in cancer catalytic therapy has been severely constrained by the insufficient endogenous H₂O₂. To address this, constructing a self-cascading nanozyme that integrates oxidase (OXD) and peroxidase (POD) activities is highly desirable yet challenging, primarily due to the difficulty in stabilizing high-content of Fe(II) within nanostructures. Herein, we report the first synthesis of mesoporous amorphous iron oxide nanospheres (aFeO_x‑N) with unprecedented high Fe (II) level (66.59%) via the confinement coordination strategy using the strong N-donor metformin. This unique structure simultaneously exhibits robust OXD-like activity for in situ H₂O₂ generation via a 2e^- oxygen reduction pathway and enhanced POD-like activity for consequent •OH production. In vitro studies verified the aFeO_x‑N‑ss‑SiO₂ (encapsulated by SiO₂ outlayer containing ─S─S─ bonds for TME responsiveness) triggered ferroptosis and prominent cell death even under hypoxic conditions. Remarkably, a single ultralow dose (5 mg·kg^-1) achieves a tumor inhibition rate of up to 96.19% in murine models, demonstrating exceptional therapeutic efficacy and biocompatibility. This work provides a novel and potent nanozyme platform for cascade catalytic tumor therapy.