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Intracellular glutathione (GSH) acts as a copper chelator to inhibit cuproptosis, so the reduction of GSH concentration is conducive to enhancing the cuproptosis of cells. In order to reduce GSH content and interfere with mitochondrial metabolism, a strategy based on calcium overload and GSH depletion to enhance cuproptosis is proposed in this study. Containing manganese (Mn) and copper (Cu) elements, CaCO<jats:sub>3<\/jats:sub> nanoparticles (NPs) are modified with MCF\u20107 cell aptamer (CaCO<jats:sub>3<\/jats:sub>\/Mn\/Cu@lip\u2010Apt). When entering the cell, CaCO<jats:sub>3<\/jats:sub>\/Mn\/Cu@lip\u2010Apt decomposed and released Mn* (Mn<jats:sup>2+<\/jats:sup>\/Mn<jats:sup>3+<\/jats:sup>\/Mn<jats:sup>4+<\/jats:sup>), Cu<jats:sup>2+<\/jats:sup> and Ca<jats:sup>2+<\/jats:sup>. The high valence Mn ion in Mn* can effectively consume GSH to produce Mn<jats:sup>2+<\/jats:sup> which catalyzed H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> to produce reactive oxygen species (ROS), while reducing the GSH concentration. The production of ROS promoted the influx of exogenous Ca<jats:sup>2+<\/jats:sup>. The large accumulation of Ca<jats:sup>2+<\/jats:sup> led to intracellular calcium overload, resulting in mitochondrial dysfunction and metabolism disorders. The depletion of GSH promoted the accumulation of Cu<jats:sup>2+<\/jats:sup>, which in turn triggered cuproptosis. This strategy showed excellent antitumor effects and provided a new way to study disease treatment.<\/jats:p>","DOI":"10.1002\/advs.202412067","type":"journal-article","created":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T00:55:41Z","timestamp":1739235341000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Nanoenhanced\u2010Cuproptosis Results From the Synergy of Calcium Overload and GSH Depletion with the Increasing of Intracellular Ca\/Mn\/Cu Ions"],"prefix":"10.1002","volume":"12","author":[{"given":"Shiwei","family":"Liu","sequence":"first","affiliation":[{"name":"School of Chemistry and Chemical Engineering Qilu University of Technology (Shandong Academy of Sciences)  Jinan 250353 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wennan","family":"Yan","sequence":"additional","affiliation":[{"name":"School of Chemistry and Chemical Engineering Qilu University of Technology (Shandong Academy of Sciences)  Jinan 250353 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyue","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Chemistry and Chemical Engineering Qilu University of Technology (Shandong Academy of Sciences)  Jinan 250353 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Chemistry and Chemical Engineering Qilu University of Technology (Shandong Academy of Sciences)  Jinan 250353 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyi","family":"Li","sequence":"additional","affiliation":[{"name":"School of Chemistry and Chemical Engineering Qilu University of Technology (Shandong Academy of Sciences)  Jinan 250353 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingshu","family":"Guo","sequence":"additional","affiliation":[{"name":"School of Chemistry and Chemical Engineering Qilu University of Technology (Shandong Academy of Sciences)  Jinan 250353 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong\u2010Yuan","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Analytical Chemistry for Life Science School of Chemistry and Chemical Engineering Nanjing University  Nanjing 210023 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9579-9318","authenticated-orcid":false,"given":"Jing\u2010Juan","family":"Xu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Analytical Chemistry for Life Science School of Chemistry and Chemical Engineering Nanjing University  Nanjing 210023 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,2,10]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1039\/C7MT00221A"},{"key":"e_1_2_9_1_2","doi-asserted-by":"publisher","DOI":"10.1039\/C8MT00219C"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-022-01229-y"},{"key":"e_1_2_9_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2023.215156"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abf0529"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-022-00653-7"},{"key":"e_1_2_9_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-022-00866-1"},{"key":"e_1_2_9_4_3","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-53135-2"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2023.215395"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2022.841814"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2023.101264"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1039\/C9CS00373H"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cej.2023.144951"},{"key":"e_1_2_9_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2020.213474"},{"key":"e_1_2_9_10_1","doi-asserted-by":"crossref","unstructured":"a)W. 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