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While conventional strategies are heavily dependent on multicomponent donors, we herein report an ultrasound\u2010responsive water\u2010soluble copolymer (<jats:bold>PSHF<\/jats:bold>) capable of releasing carbon monoxide (CO) and hydrogen sulfide (H<jats:sub>2<\/jats:sub>S) based on single\u2010component sulfur\u2010substituted 3\u2010hydroxyflavone (SHF) derivatives. Interestingly, sulfur substitution can not only greatly improve the ultrasound sensitivity but also enable the co\u2010release of CO\/H<jats:sub>2<\/jats:sub>S under mild ultrasound irradiation. The co\u2010release of CO\/H<jats:sub>2<\/jats:sub>S gasotransmitters exerts a bactericidal effect against <jats:italic>Staphylococcus aureus<\/jats:italic> and demonstrates anti\u2010inflammatory activity in lipopolysaccharide\u2010challenged macrophages. Moreover, the excellent tissue penetration of ultrasound irradiation enables the local release of CO\/H<jats:sub>2<\/jats:sub>S in the joints of septic arthritis rats, exhibiting superior therapeutic efficacy without the need for any antibiotics.<\/jats:p>","DOI":"10.1002\/anie.202314563","type":"journal-article","created":{"date-parts":[[2023,11,15]],"date-time":"2023-11-15T18:51:03Z","timestamp":1700074263000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":60,"title":["A Single\u2010Component Dual Donor Enables Ultrasound\u2010Triggered Co\u2010release of Carbon Monoxide and Hydrogen Sulfide"],"prefix":"10.1002","volume":"62","author":[{"given":"Mengdan","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Pharmacy The First Affiliated Hospital of University of Science and Technology of China (USTC), and Key Laboratory of Precision and Intelligent Chemistry Department of Polymer Science and Engineering University of Science and Technology of China  Hefei Anhui Province 230026 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Pharmacy The First Affiliated Hospital of University of Science and Technology of China (USTC), and Key Laboratory of Precision and Intelligent Chemistry Department of Polymer Science and Engineering University of Science and Technology of China  Hefei Anhui Province 230026 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiqiang","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Pharmacy The First Affiliated Hospital of University of Science and Technology of China (USTC), and Key Laboratory of Precision and Intelligent Chemistry Department of Polymer Science and Engineering University of Science and Technology of China  Hefei Anhui Province 230026 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paiyu","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Pediatrics The First Affiliated Hospital of Anhui Medical University  Hefei Anhui 230022 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shenggang","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Pediatrics The First Affiliated Hospital of Anhui Medical University  Hefei Anhui 230022 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6969-1343","authenticated-orcid":false,"given":"Jinming","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy The First Affiliated Hospital of University of Science and Technology of China (USTC), and Key Laboratory of Precision and Intelligent Chemistry Department of Polymer Science and Engineering University of Science and Technology of China  Hefei Anhui Province 230026 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,11,27]]},"reference":[{"key":"e_1_2_7_1_1","unstructured":"\u00a0"},{"key":"e_1_2_7_2_2","volume":"2016","author":"Yang G. 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