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However, its efficacy is still hampered by innate tumor defense systems that rely on adenosine triphosphate (ATP) for fuel, including damage repair, apoptosis resistance, and immune evasion. Inspired by the naturally enzymatic reaction of glucose oxidase (GOx) with glucose, here a novel \u201ctwo birds with one stone\u201d technique for amplifying enzyme\u2010mediated tumor apoptosis and enzyme\u2010promoted metabolic clearance is proposed and achieved using GOx\u2010functionalized rhenium nanoclusters\u2010doped polypyrrole (Re@ReP\u2010G). Re@ReP\u2010G reduces ATP production while increasing H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> concentrations in the tumor microenvironment through GOx\u2010induced enzymatic oxidation, which in turn results in the downregulation of defense (HSP70 and HSP90) and anti\u2010apoptotic Bcl\u20102 proteins, the upregulation of pro\u2010apoptotic Bax, and the release of cytochrome c. These processes are further facilitated by laser\u2010induced hyperthermia effect, ultimately leading to severe tumor apoptosis. As an enzymatic byproduct, H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> catalyzes the conversion of rhenium nanoclusters in Re@ReP\u2010G nanostructures into rhenate from the outside in, which accelerates their metabolic clearance in vivo. This Re@ReP\u2010G\u2010based \u201ctwo birds with one stone\u201d therapeutic strategy provides an effective tool for amplifying tumor apoptosis and safe metabolic mechanisms.<\/jats:p>","DOI":"10.1002\/advs.202308251","type":"journal-article","created":{"date-parts":[[2024,3,6]],"date-time":"2024-03-06T17:14:20Z","timestamp":1709745260000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Enzyme\u2010Empowered \u201cTwo Birds with One Stone\u201d Strategy for Amplifying Tumor Apoptosis and Metabolic Clearance"],"prefix":"10.1002","volume":"11","author":[{"given":"Hanyue","family":"Li","sequence":"first","affiliation":[{"name":"State Key Laboratory of Advanced Medical Materials and Devices Tianjin Key Laboratory of Biomedical Materials Institute of Biomedical Engineering Chinese Academy of Medical Sciences and Peking Union Medical College  Tianjin 300192 P. R. 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