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Modular design of prodrug nanoassemblies presents tremendous potential in upgrading the therapeutic index of chemotherapeutic agents. Given the biochemical vulnerability of tumor redox homeostasis, we fabricated five\u2010membered cyclic chalcogenide\u2010linked paclitaxel prodrug nanoassemblies, which realized tumor site\u2010specific activation and reshaped the pro\u2010apoptotic tumor redox homeostasis. Cyclic diselenide and cyclic disulfide bonds integrated the modification modules and response modules to minimize the utilization of non\u2010pharmacodynamic moieties and increase druggability. Importantly, the modification\u2010response integrated modules could simultaneously block the glutathione\u2010glutathione peroxidase (GSH\/GPx) antioxidant system and amplify reactive oxygen species (ROS) generation. 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Such an intelligent prodrug nanoplatform brought new perspectives for constructing advanced antitumor nanomedicines with significant clinical research value.<\/jats:p>","DOI":"10.1002\/exp.20240448","type":"journal-article","created":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T11:16:37Z","timestamp":1773141397000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Modification\u2010Response Integrated Modules Driven Cyclization\u2010Dependent Prodrug Self\u2010Assembly for Reshaping Pro\u2010Apoptotic Tumor Redox Homeostasis"],"prefix":"10.1002","volume":"6","author":[{"given":"Yixin","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Pharmaceutics Wuya College of Innovation Shenyang Pharmaceutical University  Shenyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiyi","family":"Zuo","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics Wuya 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