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Recent findings indicate that regenerating family protein 3\u03b1 (Reg3\u03b1) can promote keratinocyte proliferation and epidermal neogenesis, while also exhibiting antimicrobial properties. However, the low bioavailability significantly limits the clinical use of Reg3\u03b1 in the treatment of chronic diabetic wounds. This study presents a glucose and ROS dual\u2010responsive hydrogel loaded with Reg3\u03b1, which is synthesized by phenylboronic acid\u2010modified hyaluronic acid (HAP) and polyvinyl alcohol (PVA). The Reg3\u03b1\u2010loaded hydrogel (HAP\u2010PVA\/Reg3\u03b1), which exhibits favorable viscoelastic properties to adapt to wound application, promotes cell proliferation and demonstrates antibacterial and anti\u2010inflammatory activities without inducing cytotoxicity or hemolysis in vitro. In diabetic mice, HAP\u2010PVA\/Reg3\u03b1 effectively accelerates <jats:italic>Staphylococcus aureus<\/jats:italic> (<jats:italic>S. aureus<\/jats:italic>)\u2010infected wound healing by alleviating bacterial infection, reducing inflammation, and facilitating collagen deposition. The result of RNA\u2010seq suggests a negative regulation of M0 macrophages in the HAP\u2010PVA\/Reg3\u03b1 group, which is presumably associated with their transformation into anti\u2010inflammatory M2 macrophages. Meanwhile, serum pro\u2010inflammatory IL\u20106 level is significantly decreased in Reg3\u03b1 and HAP\u2010PVA\/Reg3\u03b1 groups. In conclusion, HAP\u2010PVA\/Reg3\u03b1 as a multifunctional hydrogel has significant potential for the treatment of chronic infected diabetic wounds.<\/jats:p>","DOI":"10.1002\/adhm.202500403","type":"journal-article","created":{"date-parts":[[2025,4,4]],"date-time":"2025-04-04T03:31:35Z","timestamp":1743737495000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Regenerating Family Protein 3\u03b1\u2010Loaded Responsive Hydrogel Accelerates Infected Diabetic Wound Healing"],"prefix":"10.1002","volume":"14","author":[{"given":"Qingyun","family":"Wu","sequence":"first","affiliation":[{"name":"School of Pharmaceutical Sciences Nanjing Tech University  Nanjing 211816 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shenglong","family":"Jiang","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences Nanjing Tech University  Nanjing 211816 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences Nanjing Tech University  Nanjing 211816 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Ren","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences Nanjing Tech University  Nanjing 211816 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Luo","sequence":"additional","affiliation":[{"name":"School of Life Science &amp; Technology China Pharmaceutical University  Nanjing 211198 China"},{"name":"State Key Laboratory of Nature Medicines China Pharmaceutical University  Nanjing 211198 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoguang","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences Nanjing Tech University  Nanjing 211816 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7859-211X","authenticated-orcid":false,"given":"Luting","family":"Yu","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences Nanjing Tech University  Nanjing 211816 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,4,2]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2020.120286"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/adma.202306292"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/adma.202305277"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/adhm.202400150"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2019-00073"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.2174\/187153008783928361"},{"key":"e_1_2_8_7_1","first-page":"7","author":"Chen Z.","year":"2019","journal-title":"Front. 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