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A systematic study of its multiple functions can in\u2010depth understand SAzymes's nature, which remains elusive. Here, we develop a novel ultrafast synthesis of sputtered SAzymes by in situ bombarding\u2010embedding technique. Using this method, sputtered copper (Cu) SAzymes (CuSA) is developed with unreported unique planar Cu\u2010C\n                    <jats:sub>3<\/jats:sub>\n                    coordinated configuration. To enhance the tumor\u2010specific targeting, we employ a bioorthogonal approach to engineer CuSA, denoted as CuSACO. CuSACO not only exhibits minimal off\u2010target toxicity but also possesses exceptional ultrahigh catalase\u2010, oxidase\u2010, peroxidase\u2010like multienzyme activities, resulting in reactive oxygen species (ROS) storm generation for effective tumor destruction. Surprisingly, CuSACO can release Cu ions in the presence of glutathione (GSH) to induce cuproptosis, enhancing the tumor treatment efficacy. Notably, CuSACO\u2032s remarkable photothermal properties enables precise photothermal therapy (PTT) on tumors. This, combined with nanozyme catalytic activities, cuproptosis and immunotherapy, efficiently inhibiting the growth of orthotopic breast tumors and gliomas, and lung metastasis. Our research highlights the potential of CuSACO as an innovative strategy to utilize multiple mechanism to enhance tumor therapeutic efficacy, broadening the exploration and development of enzyme\u2010like behavior and physiological mechanism of action of SAzymes.\n                  <\/jats:p>","DOI":"10.1002\/anie.202405937","type":"journal-article","created":{"date-parts":[[2024,4,24]],"date-time":"2024-04-24T00:29:37Z","timestamp":1713918577000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":93,"title":["Bioorthogonal Cu Single\u2010Atom Nanozyme for Synergistic Nanocatalytic Therapy, Photothermal Therapy, Cuproptosis and Immunotherapy"],"prefix":"10.1002","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8859-3466","authenticated-orcid":false,"given":"Luyan","family":"Wu","sequence":"first","affiliation":[{"name":"State Key Laboratory for Organic Electronics and Information Displays Jiangsu Key Laboratory 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National Synergetic Innovation Center for Advanced Materials (SICAM) School of Chemistry and Life Sciences Nanjing University of Posts and Telecommunications  Nanjing 210023 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Tong","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Organic Electronics and Information Displays Jiangsu Key Laboratory for Biosensors, Institute of Advanced Materials (IAM) Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM) School of Materials Science and Engineering Nanjing University of Posts and Telecommunications  Nanjing 210023 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangqi","family":"Yang","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Organic Electronics and Information Displays Jiangsu Key Laboratory for Biosensors, Institute of Advanced Materials (IAM) Jiangsu National Synergetic Innovation Center for Advanced 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