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Compared with the single atom nanozymes, the bi\u2010single\u2010atomic nanozymes obtained through sequential single\u2010atom synthesis strategy in different spaces of the same nanomaterial, can significantly improve the space utilization efficiency and catalytic capacity. In this study, bi\u2010single\u2010atom nanozymes (Zn\/Cu\u2010BSAN\u2010DOX NPs) are designed to reverse BC DOX resistance by causing damage to mitochondria of mesenchymal stem cells (MSCs) and 4T1 cells through reactive oxygen species (ROS) amplification. In situ H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> self\u2010supply is improved by releasing DOX through activating the nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs). ROS amplification is triggered by enhanced chemodynamic therapy (CDT) and sonodynamic therapy (SDT) of Zn\/Cu\u2010BSAN, which efficiently reverses the DOX resistance by breaking the hyaluronic acid (HA) barrier and DOX efflux. Furthermore, ROS amplification significantly promotes the immune improvement including DCs maturation, T cell activation, and the polarization of M1 macrophage. In summary, as \u201chexagonal\u201d anti\u2010tumor warrior, Zn\/Cu\u2010BSAN\u2010DOX NPs show great potential for multimodal DOX\u2010resistant BC therapy, which further expands the new preparation strategy and the clinical anti\u2010tumor application paradigm of single\u2010atom nanozymes.<\/jats:p>","DOI":"10.1002\/adfm.202410962","type":"journal-article","created":{"date-parts":[[2024,9,30]],"date-time":"2024-09-30T05:22:07Z","timestamp":1727673727000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Zn\/Cu Bi\u2010Single\u2010Atom Nanoplatform: Hexagonal Anti\u2010Tumor Warrior by ROS Amplification for DOX Resistance Reversal and Immune Activation"],"prefix":"10.1002","volume":"34","author":[{"given":"Tianyi","family":"Wang","sequence":"first","affiliation":[{"name":"Qingdao Municipal Hospital University of Health and Rehabilitation Sciences  Qingdao 266071 China"},{"name":"College of Chemistry and Pharmaceutical Sciences Qingdao Agricultural University  Qingdao 266100 China"}]},{"given":"Fenglan","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Chemistry and Pharmaceutical Sciences Qingdao Agricultural University  Qingdao 266100 China"}]},{"given":"Carlos F.","family":"Guimar\u00e3es","sequence":"additional","affiliation":[{"name":"3B's Research Group\u2010Research Institute on Biomaterials Biodegradables and Biomimetics University of Minho Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine Parque de Ci\u00eancia e Tecnologia  Zona Industrial da Gandra \u2013 Avepark, Barco Guimar\u00e3es 4805\u2010017 Portugal"},{"name":"ICVS\/3B's \u2013 Portuguese Government Associate Laboratory University of Minho  Guimar\u00e3es\/Braga 4704\u2010553 Portugal"}]},{"given":"Rui L.","family":"Reis","sequence":"additional","affiliation":[{"name":"3B's Research Group\u2010Research Institute on Biomaterials Biodegradables and Biomimetics University of Minho Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine Parque de Ci\u00eancia e Tecnologia  Zona Industrial da Gandra \u2013 Avepark, Barco Guimar\u00e3es 4805\u2010017 Portugal"},{"name":"ICVS\/3B's \u2013 Portuguese Government Associate Laboratory University of Minho  Guimar\u00e3es\/Braga 4704\u2010553 Portugal"}]},{"given":"Yaqian","family":"Lv","sequence":"additional","affiliation":[{"name":"School of Veterinary Medicine Qingdao Agricultural University  Qingdao 266109 China"}]},{"given":"Yingshan","family":"Qu","sequence":"additional","affiliation":[{"name":"School of Veterinary Medicine Qingdao Agricultural University  Qingdao 266109 China"}]},{"given":"Danping","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Veterinary Medicine Qingdao Agricultural University  Qingdao 266109 China"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2474-4197","authenticated-orcid":false,"given":"Qihui","family":"Zhou","sequence":"additional","affiliation":[{"name":"School of Rehabilitation Sciences and Engineering University of Health and Rehabilitation Sciences  Qingdao 266071 China"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9326-6171","authenticated-orcid":false,"given":"Xiaoying","family":"Kong","sequence":"additional","affiliation":[{"name":"College of Chemistry and Pharmaceutical Sciences Qingdao Agricultural University  Qingdao 266100 China"}]},{"given":"Jinsheng","family":"Shi","sequence":"additional","affiliation":[{"name":"Qingdao Municipal Hospital University of Health and Rehabilitation Sciences  Qingdao 266071 China"}]}],"member":"311","published-online":{"date-parts":[[2024,9,30]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202309917"},{"key":"e_1_2_8_2_1","first-page":"1","volume":"36","author":"He S.","year":"2024","journal-title":"Nat. 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