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To this end, a novel graft\u2010type copolymeric SO<jats:sub>2<\/jats:sub> prodrug, PLG\u2010<jats:italic>g<\/jats:italic>\u2010mPEG\u2010DNs, is designed and synthesized in this work. The amphiphilic polypeptides can self\u2010assemble into nanoparticles (NPs) and encapsulated Cu(II) ions by metal\u2010carboxyl coordination. In vitro release results showed that the obtained NPs\u2010Cu can respond to the acidic pH and high glutathione levels typical of a tumor microenvironment to release Cu(II) and SO<jats:sub>2<\/jats:sub> simultaneously. Both a Cu(II)\u2010triggered Fenton\u2010like reaction and the SO<jats:sub>2<\/jats:sub> gas would promote ROS production and upregulate the oxidative stress in tumor cells, leading to an enhanced killing effect towards 4T1 cancer cells compared to either Cu(II) or the NPs alone. Furthermore, the in vitro hemolysis of NPs\u2010Cu is less than 1.0% at a high concentration of 8\u00a0mg\/mL, indicating good blood compatibility and the potential for in vivo tumor inhibition application.<\/jats:p>","DOI":"10.1002\/mabi.202300429","type":"journal-article","created":{"date-parts":[[2023,11,21]],"date-time":"2023-11-21T14:13:14Z","timestamp":1700575994000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["A Novel Cu(II) Loaded Polypeptide SO<sub>2<\/sub> Prodrug Nanoformulation Combining Chemodynamic and Gas Anticancer Therapies"],"prefix":"10.1002","volume":"24","author":[{"given":"Yu","family":"Zhang","sequence":"first","affiliation":[{"name":"Key Laboratory of Polymer Ecomaterials Changchun Institute of Applied Chemistry Chinese Academy of Sciences  Changchun 130022 P. R. 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