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Chondroitin sulfate (CS), a naturally occurring glycosaminoglycan with established biocompatibility, presents an attractive scaffold for developing metal ion-functionalized biomaterials. This study reports the fabrication of chondroitin sulfate\u2013copper complex (CSCu) and chondroitin sulfate\u2013zinc complex (CSZn) through an ion exchange method, wherein Cu2+ and Zn2+ ions bind to the groups of carboxylate, sulfate, or N-acetyl from the CS backbone. The resulting complexes exhibited copper or zinc loading capacities of about 6.6% and demonstrated potent antibacterial activity against E. coli and S. aureus. The integration of CSCu or CSZn with sodium alginate yielded a hydrogel system with a higher apparent viscosity, possessing injectability and spreadability on the skin surface and a porous three-dimensional internal structure conducive to wound healing applications. In a murine model of S. aureus-infected full-thickness wounds, topical application of CSCu and CSZn hydrogels substantially accelerated wound closure, achieving 97.46% and 98.11% healing, respectively, by day 10. Additionally, treatment with CSCu or CSZn hydrogels significantly attenuated systemic inflammatory responses, as reflected in lowered serum TNF-\u03b1, IL-1\u03b2, and IL-6 alongside increased IL-10. Histological evaluation confirmed enhanced re-epithelialization and stratum spinosum formation in treated wounds. These findings establish CSCu and CSZn as a promising bioactive agent for addressing bacterial wound infections through a dual mechanism of direct antibacterial action and immunomodulatory effects, offering a valuable alternative to conventional antibiotic therapies.<\/jats:p>","DOI":"10.3390\/gels12070633","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T06:49:36Z","timestamp":1784184576000},"page":"633","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Fabrication of Chondroitin Sulfate\u2013Copper\/Zinc Complexes and Antibacterial Activity Involving Hydrogel Application in Infected Wound Healing"],"prefix":"10.3390","volume":"12","author":[{"given":"Qingshan","family":"Shen","sequence":"first","affiliation":[{"name":"Henan Key Laboratory of Zhang Zhongjing Formulae and Herbs for Immunoregulation, Zhang Zhongjing College of Chinese Medicine, Nanyang Institute of Technology, Changjiang Road 80, Nanyang 473004, China"},{"name":"School of Food and Health, Henan College of Classical Chinese Medicine, Hansheng Road 1222, Nanyang 473000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiarui","family":"Wu","sequence":"additional","affiliation":[{"name":"Henan Key Laboratory of Zhang Zhongjing Formulae and Herbs for Immunoregulation, Zhang Zhongjing College of Chinese Medicine, Nanyang Institute of Technology, Changjiang Road 80, Nanyang 473004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiawen","family":"Li","sequence":"additional","affiliation":[{"name":"Henan Key Laboratory of Zhang Zhongjing Formulae and Herbs for Immunoregulation, Zhang Zhongjing College of Chinese Medicine, Nanyang Institute of Technology, Changjiang Road 80, Nanyang 473004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujie","family":"Dong","sequence":"additional","affiliation":[{"name":"Henan Key Laboratory of Zhang Zhongjing Formulae and Herbs for Immunoregulation, Zhang Zhongjing College of Chinese Medicine, Nanyang Institute of Technology, Changjiang Road 80, Nanyang 473004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Liu","sequence":"additional","affiliation":[{"name":"Henan Key Laboratory of Zhang Zhongjing Formulae and Herbs for Immunoregulation, Zhang Zhongjing College of Chinese Medicine, Nanyang Institute of Technology, Changjiang Road 80, Nanyang 473004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9319-5828","authenticated-orcid":false,"given":"Lei","family":"Zhao","sequence":"additional","affiliation":[{"name":"Henan Key Laboratory of Zhang Zhongjing Formulae and Herbs for Immunoregulation, Zhang Zhongjing College of Chinese Medicine, Nanyang Institute of Technology, Changjiang Road 80, Nanyang 473004, China"},{"name":"School of Food and Health, Henan College of Classical Chinese Medicine, Hansheng Road 1222, Nanyang 473000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"Zhan","sequence":"additional","affiliation":[{"name":"Henan Key Laboratory of Zhang Zhongjing Formulae and Herbs for Immunoregulation, Zhang Zhongjing College of Chinese Medicine, Nanyang Institute of Technology, Changjiang Road 80, Nanyang 473004, China"},{"name":"School of Food and Health, Henan College of Classical Chinese Medicine, Hansheng Road 1222, Nanyang 473000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanli","family":"Ma","sequence":"additional","affiliation":[{"name":"Henan Key Laboratory of Zhang Zhongjing Formulae and Herbs for Immunoregulation, Zhang Zhongjing College of Chinese Medicine, Nanyang Institute of Technology, Changjiang Road 80, Nanyang 473004, China"},{"name":"School of Food and Health, Henan College of Classical Chinese Medicine, Hansheng Road 1222, Nanyang 473000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"102298","DOI":"10.1016\/j.mtbio.2025.102298","article-title":"Extracellular vesicles in chronic wound therapy: Engineering strategies and advanced delivery systems for enhanced regeneration","volume":"35","author":"Ding","year":"2025","journal-title":"Mater. 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