A Self–Cascade Nanozyme of Metformin–Stabilized Amorphous Iron Oxide With Ultrahigh Fe(II) for Potent Tumor Therapy at Ultralow Dose

The therapeutic efficacy of iron oxide nanozymes in cancer catalytic therapy has been severely constrained by the insufficient endogenous H 2 O 2 . 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 H 2 O 2 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‑SiO 2 (encapsulated by SiO 2 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.