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Combination therapies suffer from uncontrolled release and poor responsiveness to pathological cues. Here, we report a nanoparticle-cross-linked hydrogel that integrates structural integrity with environment-triggered delivery. We utilized self-assembled epigallocatechin gallate (EGCG)-tobramycin (TOB) nanoparticles as dynamic cross-linkers within a phenylboronic acid-modified gelatin network. The engineered system provides dual-stage responsiveness: the hydrogel disassembles under the hallmark hyperglycemic and acidic conditions of diabetic wounds, releasing the nanoparticles, which then dissociate under acidity to synchronize drug release. Such sequential disassembly acts as a synergistic \u201cone-two punch,\u201d allowing EGCG to scavenge ROS and remodel the inflammatory microenvironment, while TOB provides prolonged antibacterial action. In vivo, the system significantly reduced bacterial load, accelerated epithelial regeneration, and promoted high-quality wound healing. By seamlessly coupling nanocontrolled release with microenvironmental sensing, we present a precision-engineered platform for the synergistic treatment of recalcitrant diabetic wounds.<\/jats:p>","DOI":"10.1021\/acs.biomac.6c01034","type":"journal-article","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T16:04:39Z","timestamp":1784649879000},"page":"5697-5710","source":"Crossref","is-referenced-by-count":0,"title":["Nanoparticle-Cross-Linked Smart Responsive Hydrogels\nfor Antimicrobial, Anti-Inflammatory, and Antioxidant Treatment of\nDiabetic Wounds"],"prefix":"10.1021","volume":"27","author":[{"given":"Junpeng","family":"Wang","sequence":"first","affiliation":[{"name":"The First Affiliated Hospital of Wenzhou Medical University , , ,","place":["Wenzhou, China, 325035"]},{"name":"Zhengzhou University , , ,","place":["Zhengzhou, Henan, China, 450001"]},{"name":"University of Chinese Academy of Sciences , , ,","place":["Wenzhou, China, 325001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feijing","family":"Hao","sequence":"additional","affiliation":[{"name":"University of Chinese Academy of Sciences , , ,","place":["Wenzhou, China, 325001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengwei","family":"Xu","sequence":"additional","affiliation":[{"name":"University of Chinese Academy of Sciences , , ,","place":["Wenzhou, China, 325001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Lin","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Wenzhou Medical University , , ,","place":["Wenzhou, China, 325035"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongxiang","family":"Wang","sequence":"additional","affiliation":[{"name":"University of Chinese Academy of Sciences , , ,","place":["Wenzhou, China, 325001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Xing","sequence":"additional","affiliation":[{"name":"University of Chinese Academy of Sciences , , ,","place":["Wenzhou, China, 325001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8402-7486","authenticated-orcid":true,"given":"Wentao","family":"Liu","sequence":"additional","affiliation":[{"name":"Zhengzhou University , , ,","place":["Zhengzhou, Henan, China, 450001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7785-7075","authenticated-orcid":true,"given":"Hao","family":"Liu","sequence":"additional","affiliation":[{"name":"Zhengzhou University , , ,","place":["Zhengzhou, Henan, China, 450001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4483-4467","authenticated-orcid":true,"given":"Na","family":"Li","sequence":"additional","affiliation":[{"name":"University of Chinese Academy of Sciences , , ,","place":["Wenzhou, China, 325001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weidong","family":"Xia","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Wenzhou Medical University , , ,","place":["Wenzhou, China, 325035"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,21]]},"reference":[{"key":"2026081008081408000_cit1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cej.2024.154855","article-title":"Multi-Functional hydrogels\nto promote diabetic wound Healing: A review","volume":"497","author":"Yang","year":"2024","journal-title":"Chem. 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Nanobiotechnol."},{"key":"2026081008081408000_cit33","doi-asserted-by":"publisher","DOI":"10.1016\/j.cej.2024.154436","article-title":"Hydrogel-Based drug delivery systems\nfor diabetes bone defects","volume":"497","author":"Ye","year":"2024","journal-title":"Chem. Eng. J."},{"key":"2026081008081408000_cit34","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2025.148128","article-title":"Multifunctional hydrogel scaffolds\nloaded with peptides in promoting wound healing: A review","volume":"330","author":"Dong","year":"2025","journal-title":"Int. J. Biol. Macromol."},{"key":"2026081008081408000_cit35","doi-asserted-by":"publisher","DOI":"10.1016\/j.carbpol.2022.119177","article-title":"Preparation,\nproperties and drug controlled release\nof chitin-based hydrogels: An updated review","volume":"283","author":"Liao","year":"2022","journal-title":"Carbohydr. 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Mater."},{"key":"2026081008081408000_cit51","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2024.129453","article-title":"Gelatin-based dynamic\nresponse antioxidant, anti-inflammatory multifunctional hydrogel for\nenhanced diabetic wound repair","volume":"260","author":"Yang","year":"2024","journal-title":"Int. J. Biol.\nMacromol."},{"issue":"4","key":"2026081008081408000_cit52","doi-asserted-by":"publisher","first-page":"1035","DOI":"10.1007\/s40843-020-1480-3","article-title":"A smart hydrogel for\non-demand delivery of antibiotics and efficient eradication of biofilms","volume":"64","author":"Hu","year":"2021","journal-title":"Sci. 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