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Although the integrin \u03b1v\u03b23 agonist peptide FZ1 exhibits promising pro-healing activity, limited delivery control and insufficient functional versatility have restricted its clinical translation. To overcome these constraints, a pH-responsive hyaluronic acid (HA)-based hydrogel, hyaluronic acid conjugated with FZ1 peptide (HA-c-FZ1), was developed to enable intelligent acidity-triggered peptide release while integrating antimicrobial activity, reactive oxygen species (ROS) scavenging, and inflammation control within a single wound dressing platform for diabetic wound repair.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Photo-crosslinkable oxidized methacrylated HA was synthesized and covalently linked to FZ1 through a pH-labile Schiff base bond, yielding HA-c-FZ1 hydrogel at three concentrations (2%, 3%, and 4%). HA-c-FZ1 hydrogel morphology, swelling behavior, mechanical properties, peptide-loading efficiency, pH-responsive release, antioxidant activity, antibacterial activity, biocompatibility, and anti-inflammatory effects were systematically evaluated in vitro. Therapeutic efficacy was then assessed in a diabetic mouse model with infected full-thickness skin wounds through wound closure analysis, histological staining, immunofluorescence detection of macrophage polarization markers (inducible nitric oxide synthase and arginase) and angiogenic markers (alpha-smooth muscle actin and vascular endothelial growth factor), and laser speckle imaging of blood perfusion. Transcriptomic profiling, RT-qPCR, and western blotting were performed to define the molecular mechanisms underlying HA-c-FZ1-mediated wound repair.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>HA-c-FZ1 hydrogel formed a homogeneous porous hydrogel network with predictable swelling behavior, tunable mechanical performance, high FZ1 loading efficiency, and accelerated peptide release under acidic conditions. In vitro, HA-c-FZ1 hydrogel promoted keratinocyte proliferation and migration, reduced ROS accumulation, and inhibited Staphylococcus aureus and Escherichia coli survival. In infected diabetic wounds, HA-c-FZ1 hydrogel suppressed bacterial burden and accelerated wound closure, accompanied by enhanced re-epithelialization, collagen deposition, angiogenesis, and local blood perfusion. Mechanistic analyses indicated that HA-c-FZ1 hydrogel attenuated nuclear factor kappa B-associated inflammatory signaling, promoted M2 macrophage polarization, and activated focal adhesion kinase\u2013protein kinase B-dependent angiogenic responses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>HA-c-FZ1 functions as a pH-responsive hydrogel dressing that combines peptide delivery with antimicrobial, redox-regulatory, immunomodulatory, and pro-angiogenic functions. These findings position it as a therapy for chronic diabetic wound repair by simultaneously addressing infection, inflammation, oxidative stress, and vascular regeneration.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/burnst\/tkag046","type":"journal-article","created":{"date-parts":[[2026,7,5]],"date-time":"2026-07-05T11:56:04Z","timestamp":1783252564000},"source":"Crossref","is-referenced-by-count":10,"title":["Multifunctional pH-responsive HA-c-FZ1 hydrogel presents a promising therapeutic strategy for diabetic skin wounds"],"prefix":"10.1093","volume":"14","author":[{"given":"Zhe","family":"Fu","sequence":"first","affiliation":[{"name":"Department of Endocrinology, Affiliated Hospital of Yunnan University , No. 176 Qingnian Road, Wuhua District, Kunming, Yunnan 650021 ,","place":["China"]},{"name":"Key Laboratory of Skin and Mucosal Injury Repair, Regeneration and Active Peptides of Yunnan Provincial Department of Education, Regenerative Medicine Research Center, Faculty of Basic Medical Science, Kunming Medical University , No. 1168 Chunrong West Road, Chenggong District, Kunming, Yunnan 650500 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyu","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Affiliated Hospital of Yunnan University , No. 176 Qingnian Road, Wuhua District, Kunming, Yunnan 650021 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutong","family":"Wu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Skin and Mucosal Injury Repair, Regeneration and Active Peptides of Yunnan Provincial Department of Education, Regenerative Medicine Research Center, Faculty of Basic Medical Science, Kunming Medical University , No. 1168 Chunrong West Road, Chenggong District, Kunming, Yunnan 650500 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoxun","family":"Xiao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Skin and Mucosal Injury Repair, Regeneration and Active Peptides of Yunnan Provincial Department of Education, Regenerative Medicine Research Center, Faculty of Basic Medical Science, Kunming Medical University , No. 1168 Chunrong West Road, Chenggong District, Kunming, Yunnan 650500 ,","place":["China"]},{"name":"School of Nursing and Health, Nanfang College Guangzhou , No. 882 Wenquan Avenue, Conghua District, Guangzhou, Guangdong 510970 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunhan","family":"Su","sequence":"additional","affiliation":[{"name":"Key Laboratory of Skin and Mucosal Injury Repair, Regeneration and Active Peptides of Yunnan Provincial Department of Education, Regenerative Medicine Research Center, Faculty of Basic Medical Science, Kunming Medical 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,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunjian","family":"Luo","sequence":"additional","affiliation":[{"name":"Key Laboratory of Skin and Mucosal Injury Repair, Regeneration and Active Peptides of Yunnan Provincial Department of Education, Regenerative Medicine Research Center, Faculty of Basic Medical Science, Kunming Medical University , No. 1168 Chunrong West Road, Chenggong District, Kunming, Yunnan 650500 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuanqing","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Skin and Mucosal Injury Repair, Regeneration and Active Peptides of Yunnan Provincial Department of Education, Regenerative Medicine Research Center, Faculty of Basic Medical Science, Kunming Medical University , No. 1168 Chunrong West Road, Chenggong District, Kunming, Yunnan 650500 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