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Here, we develop ionic microbubbles (MB-CuTA) self-assembled by Fe3O4@CuTA nanoparticles to enhance copper ion-mediated antibiofilm therapy. Upon ultrasound activation, MB-CuTA undergoes inertial cavitation, disrupting biofilm integrity and generating a localized surge of copper ions. This process achieves a dual therapeutic effect: (1) disruption of bacterial metabolic homeostasis, thereby overcoming the intrinsic resistance of biofilms to conventional antimicrobial agents, and (2) activation of cellular immunity to effectively counteract bacterial immune evasion mechanisms. By breaking biofilm tolerance through both metabolic and immunological pathways, our strategy enables deep copper ion penetration in biofilms and effective infection clearance in both mouse implant infection and peritonitis infection models. Our approach introduces a biofilm tolerance disruption method through inducing bacterial cuproptosis-like death and cellular immunity activation, offering a promising strategy against biofilm infections.<\/jats:p>","DOI":"10.1021\/acsnano.5c08035","type":"journal-article","created":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T19:57:17Z","timestamp":1753991837000},"page":"28624-28643","source":"Crossref","is-referenced-by-count":45,"title":["Disrupting\nBiofilm Tolerance by Ionic Microbubble-Mediated\nCopper Ion Surge for Infection Clearance"],"prefix":"10.1021","volume":"19","author":[{"given":"Xiaoye","family":"Li","sequence":"first","affiliation":[{"name":"Nanjing University , , 30 Zhongyang Road , ,","place":["Nanjing, China, 210008"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Li","sequence":"additional","affiliation":[{"name":"Nanjing University , , 30 Zhongyang Road , ,","place":["Nanjing, China, 210008"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ao","family":"He","sequence":"additional","affiliation":[{"name":"Nanjing University , , 30 Zhongyang Road , ,","place":["Nanjing, China, 210008"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Dang","sequence":"additional","affiliation":[{"name":"Nanjing University , , 30 Zhongyang Road , ,","place":["Nanjing, China, 210008"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Nanjing University , , 30 Zhongyang Road , ,","place":["Nanjing, China, 210008"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minjin","family":"Wang","sequence":"additional","affiliation":[{"name":"Nanjing University , , 30 Zhongyang Road , ,","place":["Nanjing, China, 210008"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinhong","family":"Sun","sequence":"additional","affiliation":[{"name":"Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & Nanjing Medical University Affiliated Cancer Hospital , , ,","place":["Nanjing, China, 210009"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuo","family":"Dai","sequence":"additional","affiliation":[{"name":"Nanjing University , , 30 Zhongyang Road , ,","place":["Nanjing, China, 210008"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Ding","sequence":"additional","affiliation":[{"name":"Nanjing University , , 30 Zhongyang Road , ,","place":["Nanjing, China, 210008"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingben","family":"Zheng","sequence":"additional","affiliation":[{"name":"Nanjing University , , 30 Zhongyang Road , ,","place":["Nanjing, China, 210008"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongbin","family":"Mou","sequence":"additional","affiliation":[{"name":"Nanjing University , , 30 Zhongyang Road , ,","place":["Nanjing, China, 210008"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weijun","family":"Xiu","sequence":"additional","affiliation":[{"name":"National University of Singapore , , 15 Kent Ridge Cres , ,","place":["Singapore, Singapore, 119276"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2537-7950","authenticated-orcid":true,"given":"Heng","family":"Dong","sequence":"additional","affiliation":[{"name":"Nanjing University , , 30 Zhongyang Road , ,","place":["Nanjing, China, 210008"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2025,7,31]]},"reference":[{"issue":"15","key":"2026093015082270600_cit1","doi-asserted-by":"publisher","first-page":"1635","DOI":"10.1007\/s40265-019-01184-z","article-title":"Novel treatment strategies for biofilm-based infections","volume":"79","author":"Vuotto","year":"2019","journal-title":"Drugs"},{"issue":"10","key":"2026093015082270600_cit2","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1038\/s41579-022-00682-4","article-title":"Tolerance\nand resistance\nof microbial biofilms","volume":"20","author":"Ciofu","year":"2022","journal-title":"Nat. Rev. Microbiol."},{"issue":"7","key":"2026093015082270600_cit3","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1038\/s41579-022-00686-0","article-title":"Skeletal infections: Microbial pathogenesis, immunity\nand clinical management","volume":"20","author":"Masters","year":"2022","journal-title":"Nat. Rev. Microbiol."},{"issue":"1","key":"2026093015082270600_cit4","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1186\/s40824-022-00326-x","article-title":"Immunomodulatory\nbiomaterials for implant-associated infections: From conventional\nto advanced therapeutic strategies","volume":"26","author":"Dong","year":"2022","journal-title":"Biomater.\nRes."},{"issue":"3","key":"2026093015082270600_cit5","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1002\/emmm.201100123","article-title":"Return of the trojan\nhorse: Intracellular phenotype\nswitching and immune evasion by staphylococcus aureus","volume":"3","author":"Garzoni","year":"2011","journal-title":"EMBO Mol. Med."},{"key":"2026093015082270600_cit6","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1146\/annurev.mi.41.100187.002251","article-title":"Bacterial\nbiofilms in nature and\ndisease","volume":"41","author":"Costerton","year":"1987","journal-title":"Annu. Rev. 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