{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:00:52Z","timestamp":1790830852845,"version":"4.1.0"},"reference-count":38,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T00:00:00Z","timestamp":1776902400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T00:00:00Z","timestamp":1776902400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Smart Molecules"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    To overcome cisplatin resistance without increasing systemic toxicity, we rationally elaborated a glutathione\u2010activatable prodrug nanomedicine that chemically co\u2010encapsulates cisplatin and a masked protease. First, a redox\u2010labile succinimide linker (NC\u2010ss\u2010COOH) was covalently grafted onto the \u03b5\u2010amino groups of trypsin to create a \u201cpro\u2010protease\u201d (ssTrypsin) whose catalytic activity is completely silenced in circulation but instantly restored (\u226596%) upon cleavage by intratumoral GSH. Simultaneously, cisplatin was stably coordinated to the carboxyl\u2010rich backbone of cRGD\u2010PEG\u2010polyglutamic acid and carboxyl\u2010rich ssTrypsin, forming a polymer\u2013Pt(II) prodrug that prevents premature Pt\u2010GSH adduct formation. These two prodrugs co\u2010self\u2010assemble into potent anti\u2010tumor nanoconstructs that actively target \u03b1\n                    <jats:sub>v<\/jats:sub>\n                    \u03b2\n                    <jats:sub>3<\/jats:sub>\n                    \/\u03b1\n                    <jats:sub>v<\/jats:sub>\n                    \u03b2\n                    <jats:sub>5<\/jats:sub>\n                    \u2010overexpressing tumors. Upon GSH\u2010triggered activation, the dual\u2010drug combination exerts complementary actions: (i) released cisplatin directly damages DNA, while (ii) reactivated trypsin proteolytically degrades all intracellular, cytomembrane, and extracellular proteins as possible (including DNA\u2010repair proteins), collectively re\u2010sensitizing resistant cells. This \u201cprodrug\u00a0+\u00a0pro\u2010enzyme\u201d strategy yields a 2.5\u2010fold reduction in IC\n                    <jats:sub>50<\/jats:sub>\n                    against A2780DDP cells and 77% tumor suppression in vivo, all with minimal off\u2010target toxicity.\n                  <\/jats:p>","DOI":"10.1002\/smo2.70055","type":"journal-article","created":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T05:46:14Z","timestamp":1777009574000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Redox\u2010responsive dual\u2010drug nanomedicine integrating cisplatin and trypsin for synergistic reversal of tumor chemoresistance"],"prefix":"10.1002","volume":"4","author":[{"given":"Xiaolan","family":"Yin","sequence":"first","affiliation":[{"name":"School of Bioengineering Dalian University of Technology  Dalian China"},{"name":"Innovation Center of Yangtze River Delta Zhejiang University  Jiaxing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Bioengineering Dalian University of Technology  Dalian China"},{"name":"Innovation Center of Yangtze River Delta Zhejiang University  Jiaxing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Bioengineering Dalian University of Technology  Dalian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Bioengineering Dalian University of Technology  Dalian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qixian","family":"Chen","sequence":"additional","affiliation":[{"name":"Provincial Key Laboratory of Interdisciplinary Medical Engineering for Gastrointestinal Carcinoma Liaoning Cancer Hospital &amp; 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