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To address this, constructing a self\u2013cascading nanozyme that integrates oxidase (OXD) and peroxidase (POD) activities is highly desirable yet challenging, primarily due to the difficulty in stabilizing high\u2013content of Fe(II) within nanostructures. Herein, we report the first synthesis of mesoporous amorphous iron oxide nanospheres (aFeO\n                    <jats:sub>x<\/jats:sub>\n                    \u2011N) with unprecedented high Fe (II) level (66.59%) via the confinement coordination strategy using the strong N\u2013donor metformin. This unique structure simultaneously exhibits robust OXD\u2013like activity for in situ H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    generation via a 2e\n                    <jats:sup>\u2212<\/jats:sup>\n                    oxygen reduction pathway and enhanced POD\u2013like activity for consequent \u2022OH production. In vitro studies verified the aFeO\n                    <jats:sub>x<\/jats:sub>\n                    \u2011N\u2011ss\u2011SiO\n                    <jats:sub>2<\/jats:sub>\n                    (encapsulated by SiO\n                    <jats:sub>2<\/jats:sub>\n                    outlayer containing \u2500S\u2500S\u2500 bonds for TME responsiveness) triggered ferroptosis and prominent cell death even under hypoxic conditions. Remarkably, a single ultralow dose (5\u00a0mg\u00b7kg\n                    <jats:sup>\u22121<\/jats:sup>\n                    ) 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.\n                  <\/jats:p>","DOI":"10.1002\/anie.7061041","type":"journal-article","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T01:01:39Z","timestamp":1780966899000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Self\u2013Cascade Nanozyme of Metformin\u2013Stabilized Amorphous Iron Oxide With Ultrahigh Fe(II) for Potent Tumor Therapy at Ultralow Dose"],"prefix":"10.1002","volume":"65","author":[{"given":"Wanxuan","family":"Xiang","sequence":"first","affiliation":[{"name":"Department of Chemistry School of Chemistry and Chemical Engineering Centre of Free Electron Laser &amp; High Magnetic Field Key Laboratory of Structure and Functional Regulation of Hybrid Materials Ministry of Education Key Laboratory of Functional Inorganic Materials Chemistry of Anhui Province Key Laboratory of Chemistry for Inorganic\/Organic Hybrid Functionalized Materials of Anhui Province Anhui University  Hefei P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoju","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Chemistry Key Laboratory of Material Chemistry for Energy Conversion and Storage Huazhong University of Science and Technology Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica School of Chemistry and Chemical Engineering Huazhong University of Science and Technology  Wuhan P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuchun","family":"Liu","sequence":"additional","affiliation":[{"name":"Hefei National Research Center for Physical Sciences at the Microscale School of Chemistry and Materials Science University of Science and Technology of China  Hefei Anhui P. R. 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