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Herein, we report self\u2010immolative amphiphilic poly(ferrocenes), <jats:bold>BP<\/jats:bold><jats:sup><jats:italic><jats:bold>nbs<\/jats:bold><\/jats:italic><\/jats:sup><jats:bold>\u2010Fc<\/jats:bold>, composed by self\u2010immolative backbone and aminoferrocene (AFc) side chains as well as end\u2010capping poly(ethylene glycol) monomethyl ether. Upon triggering by tumor acidic milieu, the <jats:bold>BP<\/jats:bold><jats:sup><jats:italic><jats:bold>nbs<\/jats:bold><\/jats:italic><\/jats:sup><jats:bold>\u2010Fc<\/jats:bold> nanoparticles readily degrade to release azaquinone methide (AQM) moieties, which can rapidly deplete intracellular glutathione (GSH) to cascade release AFc. Furthermore, both AFc and its product Fe<jats:sup>2+<\/jats:sup> can catalyze intracellular hydrogen peroxide (H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>) into highly reactive hydroxyl radicals (\u22c5OH), thus amplifying the oxidative stress of tumor cells. Rational synergy of GSH depletion and \u22c5OH burst can efficiently inhibit tumor growth by the SIPs in vitro and in vivo. This work provides an elegant design to adopt innate tumor milieu\u2010triggerable SIPs degradation to boost cellular oxidative stress, which is a promising candidate for precision medicine.<\/jats:p>","DOI":"10.1002\/anie.202303829","type":"journal-article","created":{"date-parts":[[2023,5,26]],"date-time":"2023-05-26T16:59:27Z","timestamp":1685120367000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Self\u2010Immolative Amphiphilic Poly(ferrocenes) for Synergistic Amplification of Oxidative Stress in Tumor Therapy"],"prefix":"10.1002","volume":"62","author":[{"given":"Jie","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Pharmacy The First Affiliated Hospital of USTC Division of Life Sciences and Medicine, and Key Laboratory of Precision and Intelligent Chemistry University of Science and Technology of China  96 Jinzhai Road 230026 Hefei Anhui Province 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