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Herein, we developed a self-amplifying cascade enzymatic nanoplatform (ReS2@GOx) for nanocatalytic tumor therapy by orchestrating metabolic reprogramming and oxidative stress. This nanoplatform integrates rhenium disulfide (ReS2) nanozyme possessing trimodal enzyme-mimetic activities (catalase (CAT)-like, nicotinamide adenine dinucleotide (NADH) oxidase (NOX)-like, and glutathione oxidase (GSHOx)-like activities) with glucose oxidase (GOx), enabling three interlocked therapeutic actions: (1) external energy-independent singlet oxygen (1O2) generation through ReS2-mediated hydrogen peroxide (H2O2) conversion involving a superoxide anion (\u2022O2-) intermediate; (2) attenuation of metabolic circuits through NADH oxidation and glutathione depletion; and (3) a cyclic cascade reaction driven by GOx-mediated glucose oxidation and H2O2 production, coupled with CAT-mediated H2O2-to-O2 conversion, sustaining glucose oxidation and NADH consumption. Mechanistic studies reveal a noncanonical 1O2 generation pathway involving electron shuttle-mediated \u2022O2\u2013 conversion, establishing a redox loop fueled by endogenous substrates (e.g., glucose, NADH). The coordinated enzymatic triad achieves dual tumor suppression, including blocking adenosine triphosphate (ATP) production by inhibiting glycolysis\/oxidative phosphorylation (OXPHOS) and inducing lipid peroxidation. This work demonstrates a nanocatalytic tumor therapy strategy that orchestrates tumor metabolism to potentiate oxidative lethality, highlighting the therapeutic potential of metabolic regulation for tumor treatment.<\/jats:p>","DOI":"10.1021\/acsnano.6c09137","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:36:48Z","timestamp":1791297408000},"page":"27748-27761","source":"Crossref","is-referenced-by-count":0,"title":["Self-Amplifying\nCascade Enzymatic Nanoplatform Orchestrating\nMetabolic Reprogramming and Oxidative Stress for Antitumor Therapy"],"prefix":"10.1021","volume":"20","author":[{"given":"Yusheng","family":"Chen","sequence":"first","affiliation":[{"name":"Donghua University , , ,","place":["Shanghai, China, 201620"]},{"name":"Shenzhen University , , ,","place":["Shenzhen, China, 518055"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Liu","sequence":"additional","affiliation":[{"name":"Shenzhen University , , ,","place":["Shenzhen, China, 518055"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengluan","family":"Gao","sequence":"additional","affiliation":[{"name":"Donghua University , , ,","place":["Shanghai, China, 201620"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingjian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Donghua University , , ,","place":["Shanghai, China, 201620"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hengke","family":"Liu","sequence":"additional","affiliation":[{"name":"Shenzhen University , , ,","place":["Shenzhen, China, 518055"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5497-5706","authenticated-orcid":true,"given":"Shan","family":"Lei","sequence":"additional","affiliation":[{"name":"Shenzhen University , , ,","place":["Shenzhen, China, 518055"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9865-2098","authenticated-orcid":true,"given":"Jing","family":"Lin","sequence":"additional","affiliation":[{"name":"Shenzhen University , , ,","place":["Shenzhen, China, 518055"]},{"name":"Shenzhen University , , ,","place":["Shenzhen, China, 518055"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5566-5091","authenticated-orcid":true,"given":"Rujia","family":"Zou","sequence":"additional","affiliation":[{"name":"Donghua University , , ,","place":["Shanghai, China, 201620"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3651-7813","authenticated-orcid":true,"given":"Peng","family":"Huang","sequence":"additional","affiliation":[{"name":"Shenzhen University , , ,","place":["Shenzhen, China, 518055"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,10,6]]},"reference":[{"key":"2026102008163945400_cit1","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1038\/s41586-022-05030-3","article-title":"Brown-Fat-Mediated Tumour Suppression\nby Cold-Altered Global Metabolism","volume":"608","author":"Seki","year":"2022","journal-title":"Nature"},{"key":"2026102008163945400_cit2","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1038\/nature11066","article-title":"AMPK Regulates\nNADPH Homeostasis\nto Promote Tumour Cell Survival during Energy Stress","volume":"485","author":"Jeon","year":"2012","journal-title":"Nature"},{"issue":"1","key":"2026102008163945400_cit3","doi-asserted-by":"publisher","first-page":"4554","DOI":"10.1038\/s41467-022-32101-w","article-title":"Metabolic Reprogramming from Glycolysis\nto Fatty Acid Uptake and Beta-Oxidation in Platinum-Resistant Cancer\nCells","volume":"13","author":"Tan","year":"2022","journal-title":"Nat. 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