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Organelle\u2010targeting therapies are important tactics for precision medicine, allowing for efficient tumor treatment and reduced off\u2010target toxicity. Herein, a mitochondria\u2010targeting and hypoxia\u2010activatable nanoprodrug (POPZ NPs) is prepared. The N\u2010oxide groups of POPZ NPs can successfully target mitochondria and are reduced to tertiary amines by Cytochrome P450 enzymes (CYP450s), which are highly expressed in hypoxic tumors and located in the inner mitochondrial membranes. Biocompatible POPZ NPs can become cytotoxic and produce type\u2010I photodynamic activities and enhance photothermal properties after reduction by CYP450s. The tumor\u2010specific activatable prodrug reveals potent efficacy for tumor elimination without causing systemic toxicity. This work may provide a paradigm for achieving precision medicine as well as more convenient and feasible tumor combination therapy.<\/jats:p>","DOI":"10.1002\/adma.202412376","type":"journal-article","created":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T12:15:42Z","timestamp":1758111342000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["A Hypoxia\u2010Activatable Prodrug for Targeted Combination Therapy of Hepatoma"],"prefix":"10.1002","volume":"38","author":[{"given":"Hongyu","family":"Wang","sequence":"first","affiliation":[{"name":"Key Laboratory of Polymer Ecomaterials Changchun Institute of Applied Chemistry Chinese Academy of Sciences  Changchun Jilin 130022 P. R. China"},{"name":"School of Applied Chemistry and Engineering University of Science and Technology of China  Hefei Anhui 230026 P. R. 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