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To address this, we designed a camptothecin (CPT) dimeric prodrug with a hybrid \u2212S\u2013Se\u2013S\u2013 linker (CPT\u2013S\u2013Se-S-CPT). It self-assembles into uniform nanoparticles (SSeSCPT NPs) with dual redox-responsive release triggered by glutathione and reactive oxygen species. Selenium plays dual synergistic roles: it enhances cellular uptake and pharmacokinetics while reducing systemic toxicity; it also acts as a redox-active center to amplify oxidative stress, activating p38\/MAPK and unfolded protein response pathways, thereby inducing p53-independent apoptosis and overcoming drug resistance. In vivo, SSeSCPT NPs prolong plasma half-life, achieve efficient tumor accumulation via the EPR effect, and show potent antitumor activity in p53 mutant gastric cancer models. Surface selenium groups recognize Toll-like receptor 4 (TLR4) overexpressed on tumor cells, promoting clathrin\/caveolin-mediated endocytosis and bypassing EPR size limitations. This nanoplatform integrates CPT chemotherapy, selenium intervention, and the p53 mutation background into a single system, establishing a toxicity-controlled, efficacy-enhanced strategy. It also reveals how selenium-based nanomaterials remodel redox homeostasis, bypass p53 deficiency, and reprogram apoptotic networks. This work provides mechanistic insights and translational directions for precision therapy of p53 mutant gastrointestinal malignancies.<\/jats:p>","DOI":"10.1021\/acsnano.6c06164","type":"journal-article","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T13:55:38Z","timestamp":1784642138000},"page":"21263-21280","source":"Crossref","is-referenced-by-count":0,"title":["Selenide-Bridged\nRedox-Responsive Nanoparticles: A\nSynergistic Strategy to Overcome p53 Mutation-Mediated Drug Resistance\nin Gastric Cancer"],"prefix":"10.1021","volume":"20","author":[{"given":"Cuiman","family":"Tang","sequence":"first","affiliation":[{"name":"Northeast Forestry University , , ,","place":["Harbin, People\u2019s Republic of China, 150040"]},{"name":"Northeast Forestry University , , ,","place":["Harbin, People\u2019s Republic of China, 150040"]},{"name":"Heilongjiang Provincial Key Laboratory of the Ecological Utilization of Forestry-Based Active Substances , ,","place":["Harbin, People\u2019s Republic of China, 150040"]},{"name":"National Engineering Laboratory of Bio Resource Eco Utilization , ,","place":["Harbin, People\u2019s Republic of China, 150040"]},{"name":"Northeast Forestry University , , ,","place":["Harbin, People\u2019s Republic of China, 150040"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongjuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Northeast Forestry University , , ,","place":["Harbin, People\u2019s Republic of China, 150040"]},{"name":"Northeast Forestry University , , ,","place":["Harbin, People\u2019s Republic of China, 150040"]},{"name":"Heilongjiang Provincial Key Laboratory of the Ecological Utilization of Forestry-Based Active Substances , ,","place":["Harbin, People\u2019s Republic of China, 150040"]},{"name":"National Engineering Laboratory of Bio Resource Eco Utilization , ,","place":["Harbin, People\u2019s Republic of China, 150040"]},{"name":"Northeast Forestry University , , ,","place":["Harbin, People\u2019s Republic of China, 150040"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yankun","family":"Liu","sequence":"additional","affiliation":[{"name":"Northeast Forestry University , , ,","place":["Harbin, People\u2019s Republic of China, 150040"]},{"name":"Northeast Forestry University , , ,","place":["Harbin, People\u2019s Republic of China, 150040"]},{"name":"Heilongjiang Provincial Key Laboratory of the Ecological Utilization of Forestry-Based Active Substances , ,","place":["Harbin, People\u2019s Republic of China, 150040"]},{"name":"National Engineering Laboratory of Bio Resource Eco Utilization , ,","place":["Harbin, People\u2019s Republic of China, 150040"]},{"name":"Northeast Forestry University , , ,","place":["Harbin, People\u2019s Republic of China, 150040"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhicun","family":"Liu","sequence":"additional","affiliation":[{"name":"Northeast Forestry University , , ,","place":["Harbin, People\u2019s Republic of China, 150040"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Zhu","sequence":"additional","affiliation":[{"name":"Northeast Forestry University , , ,","place":["Harbin, People\u2019s Republic of China, 150040"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4602-1934","authenticated-orcid":true,"given":"Xiuhua","family":"Zhao","sequence":"additional","affiliation":[{"name":"Northeast Forestry University , , ,","place":["Harbin, People\u2019s Republic of China, 150040"]},{"name":"Northeast Forestry University , , ,","place":["Harbin, People\u2019s Republic of China, 150040"]},{"name":"Northeast Forestry University , , ,","place":["Harbin, People\u2019s Republic of China, 150040"]},{"name":"Heilongjiang Provincial Key Laboratory of the Ecological Utilization of Forestry-Based Active Substances , ,","place":["Harbin, People\u2019s Republic of China, 150040"]},{"name":"National Engineering Laboratory of Bio Resource Eco Utilization , ,","place":["Harbin, People\u2019s Republic of China, 150040"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,21]]},"reference":[{"key":"2026080409280837600_cit1","doi-asserted-by":"publisher","DOI":"10.1002\/adfm.202527134","article-title":"Ultrasound-Triggered Diselenide Bonds\nScission for On-Demand Drug Release in Osteoarthritis Therapy","volume":"36","author":"Zhou","year":"2026","journal-title":"Adv. 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