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Nonselective distribution of cytotoxic agents leads to suboptimal drug concentrations within tumor tissues, causing systemic toxicity in healthy organs. Tumor microenvironment\u2010responsive nanoplatforms offer a promising strategy for enhancing specificity and efficacy. This study demonstrates the successful development of a nanodrug delivery system, CASS@PTX nanoparticles, where CASS is a cinnamaldehyde\u2010based, disulfide\u2010containing polymer engineered with dual\u2010stimulus responsiveness to glutathione (GSH) depletion and reactive oxygen species (ROS) amplification. This system disrupts intracellular redox homeostasis in tumor cells, triggering the release of encapsulated paclitaxel (PTX) while enhancing chemotherapeutic efficacy through redox\u2010dependent sensitization. GSH consumption and ROS overproduction create a prooxidative microenvironment that enhances PTX\u2010induced apoptosis. Preclinical validation using in vitro cytotoxicity assays and in vivo tumor models demonstrates potent synergistic anti\u2010tumor effects with minimal systemic toxicity. This cascading ROS self\u2010generation strategy represents a promising approach for overcoming multidrug resistance and improving the therapeutic outcomes of cancer chemotherapy.<\/jats:p>","DOI":"10.1002\/adhm.71002","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T20:54:06Z","timestamp":1773003246000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Redox Dual\u2010Responsive Drug Delivery System with Cascade of Reactive Oxygen Species Self\u2010Generation for Enhanced Cancer Chemotherapy"],"prefix":"10.1002","volume":"15","author":[{"given":"Ling","family":"Zeng","sequence":"first","affiliation":[{"name":"Scientific Research Center Department of Pharmacy The Seventh Affiliated Hospital Sun Yat\u2010sen University  Shenzhen China"},{"name":"Department of Laboratory Medicine The Second Xiangya Hospital Central South University  Changsha 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