{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T12:24:41Z","timestamp":1786969481203,"version":"build-2736575974"},"reference-count":39,"publisher":"American Chemical Society (ACS)","issue":"16","license":[{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Basic Research Program of China (973 Program)","doi-asserted-by":"crossref","award":["2023YFC23606003"],"award-info":[{"award-number":["2023YFC23606003"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China (NSFC)","doi-asserted-by":"crossref","award":["82370781"],"award-info":[{"award-number":["82370781"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Background: Diabetic foot ulcers (DFUs) represent a prevalent complication of diabetes mellitus, featuring elevated incidence, high amputation risk, and heavy economic medical burdens. Current clinical treatments for DFUs primarily focus on comprehensive care with limited efficacy. Quercetin, a flavonoid compound with antioxidant properties, has shown potential therapeutic effects in inflammatory-related diseases. Objective: investigate the role of quercetin in activating Foxo3-induced macrophage autophagy and promoting M2 polarization in DFUs, and to evaluate the therapeutic efficacy of a quercetin co-crosslinked hydrogel for sustained drug delivery. Methods: Animal models of DFUs were established to validate quercetin\u2019s ability to accelerate epithelialization and angiogenesis. RNA-seq screening revealed enhanced macrophage autophagy and upregulated Foxo3 expression under quercetin treatment. To optimize clinical applicability, a GelMA-Quercetin co-cross-linked hydrogel was developed for localized and sustained drug release. The in vivo therapeutic efficacy was evaluated by measuring wound closure, performing histological assessment, and analyzing macrophage polarization-related markers. Results: Quercetin markedly improved diabetic wound repair by facilitating M2 macrophage polarization, promoting ROS elimination, and inhibiting NLRP3 inflammasome activation. The GelMA-Quercetin hydrogel demonstrated sustained drug release, achieving 80% cumulative release within 48 h, and markedly improved wound closure compared to saline and GelMA-only controls. Hydrogel-treated wounds exhibited reduced inflammation, increased angiogenesis, and accelerated epithelial regeneration. Conclusion: This study demonstrates that quercetin activates the Foxo3-autophagy axis to drive M2 macrophage polarization, thereby resolving chronic inflammation in DFUs. The GelMA-Quercetin hydrogel provides a clinically translatable strategy for localized therapy, combining sustained drug delivery with enhanced wound healing. These findings highlight quercetin\u2019s dual role as a molecular regulator and hydrogel-based therapeutic agent for DFUs.<\/jats:p>","DOI":"10.1021\/acsabm.6c00157","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T14:38:47Z","timestamp":1785854327000},"page":"7312-7325","source":"Crossref","is-referenced-by-count":0,"title":["Sustained-Release GelMA-Quercetin Hydrogel Accelerates Diabetic Foot Ulcer Healing via Foxo3-Mediated Macrophage Autophagy and M2 Polarization"],"prefix":"10.1021","volume":"9","author":[{"given":"Tianyi","family":"Ni","sequence":"first","affiliation":[{"name":"The First Affiliated Hospital with Nanjing Medical University , , , ,","place":["Nanjing, Jiangsu, P. R. China, 210000"]},{"name":"The Second Affiliated Hospital of Nanjing Medical University, Nanjing Medical University , , , ,","place":["Nanjing, Jiangsu, P. R. China, 210011"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Zhang","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital with Nanjing Medical University , , , ,","place":["Nanjing, Jiangsu, P. R. China, 210000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingying","family":"Wang","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital with Nanjing Medical University , , , ,","place":["Nanjing, Jiangsu, P. R. China, 210000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Yi","sequence":"additional","affiliation":[{"name":"The Affiliated Friendship Plastic Surgery Hospital of Nanjing Medical University , , , ,","place":["Nanjing, Jiangsu, P.R. China, 210000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liying","family":"Tu","sequence":"additional","affiliation":[{"name":"The Affiliated Friendship Plastic Surgery Hospital of Nanjing Medical University , , , ,","place":["Nanjing, Jiangsu, P.R. China, 210000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaowei","family":"Sun","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital with Nanjing Medical University , , , ,","place":["Nanjing, Jiangsu, P. R. China, 210000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tinghong","family":"Xiang","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital with Nanjing Medical University , , , ,","place":["Nanjing, Jiangsu, P. R. China, 210000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiwen","family":"Gao","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital with Nanjing Medical University , , , ,","place":["Nanjing, Jiangsu, P. R. China, 210000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhechen","family":"Zhu","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital with Nanjing Medical University , , , ,","place":["Nanjing, Jiangsu, P. R. China, 210000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Yan","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital with Nanjing Medical University , , , ,","place":["Nanjing, Jiangsu, P. R. China, 210000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongqing","family":"Wei","sequence":"additional","affiliation":[{"name":"The Second Affiliated Hospital of Nanjing Medical University, Nanjing Medical University , , , ,","place":["Nanjing, Jiangsu, P. R. China, 210011"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6665-8660","authenticated-orcid":true,"given":"Ming","family":"Wang","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital with Nanjing Medical University , , , ,","place":["Nanjing, Jiangsu, P. R. China, 210000"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,1]]},"reference":[{"key":"2026081707161512100_cit1","doi-asserted-by":"publisher","DOI":"10.1016\/j.diabres.2021.109119","article-title":"IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045","volume":"183","author":"Sun","year":"2022","journal-title":"Diabetes Res. Clin. Pract."},{"issue":"9","key":"2026081707161512100_cit2","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2021.22607","article-title":"Effect of a Novel Macrophage-Regulating Drug on Wound Healing in Patients With Diabetic Foot Ulcers: A Randomized Clinical Trial","volume":"4","author":"Huang","year":"2021","journal-title":"JAMA Netw. Open."},{"issue":"1","key":"2026081707161512100_cit3","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1186\/s12933-022-01535-3","article-title":"Circulating levels of AGEs and soluble RAGE isoforms are associated with all-cause mortality and development of cardiovascular complications in type 2 diabetes: a retrospective cohort study","volume":"21","author":"Sabbatinelli","year":"2022","journal-title":"Cardiovasc. Diabetol."},{"issue":"6","key":"2026081707161512100_cit4","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD011038.pub2","article-title":"Topical antimicrobial agents for treating foot ulcers in people with diabetes","volume":"6","author":"Dumville","year":"2017","journal-title":"Cochrane Database Syst. Rev."},{"issue":"1","key":"2026081707161512100_cit5","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1001\/jama.2023.10578","article-title":"Diabetic Foot Ulcers: A Review","volume":"330","author":"Armstrong","year":"2023","journal-title":"JAMA"},{"issue":"4","key":"2026081707161512100_cit6","doi-asserted-by":"publisher","first-page":"530","DOI":"10.1111\/j.1742-481X.2008.00457.x","article-title":"The pro-inflammatory environment in recalcitrant diabetic foot wounds","volume":"5","author":"Acosta","year":"2008","journal-title":"Int. Wound J."},{"issue":"12","key":"2026081707161512100_cit7","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD001488.pub5","article-title":"Patient education for preventing diabetic foot ulceration","volume":"2014","author":"Dorresteijn","year":"2014","journal-title":"Cochrane Database Syst. Rev."},{"issue":"585","key":"2026081707161512100_cit8","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abe4839","article-title":"Advanced bandages for diabetic wound healing","volume":"13","author":"Matoori","year":"2021","journal-title":"Sci. Transl. Med."},{"issue":"3","key":"2026081707161512100_cit9","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1177\/0141076816688346","article-title":"Prevention and treatment of diabetic foot ulcers","volume":"110","author":"Lim","year":"2017","journal-title":"J. R. Soc. Med."},{"issue":"48","key":"2026081707161512100_cit10","doi-asserted-by":"publisher","DOI":"10.1002\/adma.202306632","article-title":"An Immunomodulatory Hydrogel by Hyperthermia-Assisted Self-Cascade Glucose Depletion and ROS Scavenging for Diabetic Foot Ulcer Wound Therapeutics","volume":"35","author":"Qi","year":"2023","journal-title":"Adv. Mater."},{"key":"2026081707161512100_cit11","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/j.trsl.2021.05.006","article-title":"Macrophage polarization and diabetic wound healing","volume":"236","author":"Louiselle","year":"2021","journal-title":"Transl. Res."},{"key":"2026081707161512100_cit12","doi-asserted-by":"publisher","DOI":"10.12703\/p6-13","article-title":"The M1 and M2 paradigm of macrophage activation: time for reassessment","volume":"6","author":"Martinez","year":"2014","journal-title":"F1000Prime Rep."},{"key":"2026081707161512100_cit13","doi-asserted-by":"publisher","DOI":"10.1093\/burnst\/tkag005","article-title":"Multifunctional nanofibrous membranes enhance diabetic wound healing by inhibiting endothelial pyroptosis and regulating macrophage polarization","volume":"14","author":"Deng","year":"2026","journal-title":"Burns Trauma"},{"key":"2026081707161512100_cit14","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2022.175407","article-title":"Quercetin alleviates ferroptosis accompanied by reducing M1 macrophage polarization during neutrophilic airway inflammation","volume":"938","author":"Wang","year":"2023","journal-title":"Eur. J. Pharmacol."},{"issue":"1","key":"2026081707161512100_cit15","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1186\/s13287-018-1128-2","article-title":"Human liver stem cells attenuate concanavalin A-induced acute liver injury by modulating myeloid-derived suppressor cells and CD4(+) T cells in mice","volume":"10","author":"Bi","year":"2019","journal-title":"Stem Cell Res. Ther."},{"issue":"1","key":"2026081707161512100_cit16","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1002\/term.2772","article-title":"Macrophage functions in wound healing","volume":"13","author":"Kloc","year":"2019","journal-title":"J. Tissue Eng. Regen. Med."},{"issue":"4","key":"2026081707161512100_cit17","doi-asserted-by":"publisher","first-page":"1577","DOI":"10.1007\/s10565-022-09748-8","article-title":"WDR74 facilitates TGF-\u03b2\/Smad pathway activation to promote M2 macrophage polarization and diabetic foot ulcer wound healing in mice","volume":"39","author":"Geng","year":"2023","journal-title":"Cell Biol. Toxicol."},{"issue":"Pt A","key":"2026081707161512100_cit18","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2024.112983","article-title":"MCC950 promotes diabetic wound healing through modulating macrophage polarization in an MDSC-dependent manner","volume":"142","author":"Yan","year":"2024","journal-title":"Int. Immunopharmacol."},{"issue":"3","key":"2026081707161512100_cit19","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2024.167640","article-title":"Exosomes derived from fibroblasts in DFUs delay wound healing by delivering miR-93-5p to target macrophage ATG16L1","volume":"1871","author":"Xu","year":"2025","journal-title":"Biochim. Biophys. Acta, Mol. Basis Dis."},{"key":"2026081707161512100_cit20","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/j.actbio.2025.02.046","article-title":"A calcitonin gene-related peptide co-crosslinked hydrogel promotes diabetic wound healing by regulating M2 macrophage polarization and angiogenesis","volume":"196","author":"Li","year":"2025","journal-title":"Acta Biomater."},{"issue":"19","key":"2026081707161512100_cit21","doi-asserted-by":"publisher","DOI":"10.3390\/molecules27196545","article-title":"Quercetin: Its Antioxidant Mechanism, Antibacterial Properties and Potential Application in Prevention and Control of Toxipathy","volume":"27","author":"Qi","year":"2022","journal-title":"Molecules"},{"issue":"1","key":"2026081707161512100_cit22","doi-asserted-by":"publisher","DOI":"10.3390\/nu14010067","article-title":"Regulatory Effects of Quercetin on M1\/M2 Macrophage Polarization and Oxidative\/Antioxidative Balance","volume":"14","author":"Tsai","year":"2021","journal-title":"Nutrients"},{"issue":"1","key":"2026081707161512100_cit23","doi-asserted-by":"publisher","first-page":"1.e1","DOI":"10.1016\/j.jaad.2013.06.055","article-title":"Diabetic foot ulcers: Part I. Pathophysiology and prevention","volume":"70","author":"Alavi","year":"2014","journal-title":"J. Am. Acad. Dermatol."},{"issue":"24","key":"2026081707161512100_cit24","doi-asserted-by":"publisher","first-page":"2367","DOI":"10.1056\/NEJMra1615439","article-title":"Diabetic Foot Ulcers and Their Recurrence","volume":"376","author":"Armstrong","year":"2017","journal-title":"N. Engl. J. Med."},{"issue":"5","key":"2026081707161512100_cit25","doi-asserted-by":"publisher","first-page":"1080","DOI":"10.1021\/acs.accounts.0c00864","article-title":"Strategy for Treatment of Infected Diabetic Foot Ulcers","volume":"54","author":"Chang","year":"2021","journal-title":"Acc. Chem. Res."},{"key":"2026081707161512100_cit26","doi-asserted-by":"publisher","DOI":"10.1017\/s1462399409000945","article-title":"Inflammation and neuropeptides: the connection in diabetic wound healing","volume":"11","author":"Pradhan","year":"2009","journal-title":"Expert Rev. Mol. Med."},{"issue":"1","key":"2026081707161512100_cit27","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1038\/s41467-021-27801-8","article-title":"Single cell transcriptomic landscape of diabetic foot ulcers","volume":"13","author":"Theocharidis","year":"2022","journal-title":"Nat. Commun."},{"key":"2026081707161512100_cit28","doi-asserted-by":"publisher","DOI":"10.2337\/dc07-1974","article-title":"Neurovascular factors in wound healing in the foot skin of type 2 diabetic subjects: response to Krishnan et al.","volume":"31","author":"Catrina","year":"2008","journal-title":"Diabetes Care"},{"key":"2026081707161512100_cit29","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1216321","article-title":"Exploring the contribution of pro-inflammatory cytokines to impaired wound healing in diabetes","volume":"14","author":"Nirenjen","year":"2023","journal-title":"Front. Immunol."},{"issue":"2","key":"2026081707161512100_cit30","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1080\/1061186x.2016.1207650","article-title":"Reactive oxygen species: sources, consequences and targeted therapy in type 2 diabetes","volume":"25","author":"Panigrahy","year":"2017","journal-title":"J. Drug Target."},{"issue":"5","key":"2026081707161512100_cit31","doi-asserted-by":"publisher","first-page":"991","DOI":"10.1111\/jre.12912","article-title":"Hyperglycemia modulates M1\/M2 macrophage polarization via reactive oxygen species overproduction in ligature-induced periodontitis","volume":"56","author":"Zhang","year":"2021","journal-title":"J. Periodontal Res."},{"issue":"3","key":"2026081707161512100_cit32","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1016\/j.jdermsci.2019.11.004","article-title":"High glucose environment induces M1 macrophage polarization that impairs keratinocyte migration via TNF-\u03b1: An important mechanism to delay the diabetic wound healing","volume":"96","author":"Huang","year":"2019","journal-title":"J. Dermatol. Sci."},{"key":"2026081707161512100_cit33","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1016\/j.bcp.2018.05.007","article-title":"Quercetin ameliorates kidney injury and fibrosis by modulating M1\/M2 macrophage polarization","volume":"154","author":"Lu","year":"2018","journal-title":"Biochem. Pharmacol."},{"issue":"8","key":"2026081707161512100_cit34","doi-asserted-by":"publisher","first-page":"1879","DOI":"10.1080\/15548627.2021.2007027","article-title":"CDK9 inhibition blocks the initiation of PINK1-PRKN-mediated mitophagy by regulating the SIRT1-FOXO3-BNIP3 axis and enhances the therapeutic effects involving mitochondrial dysfunction in hepatocellular carcinoma","volume":"18","author":"Yao","year":"2022","journal-title":"Autophagy"},{"issue":"7","key":"2026081707161512100_cit35","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1038\/s41580-020-0230-3","article-title":"Reactive oxygen species (ROS) as pleiotropic physiological signalling agents","volume":"21","author":"Sies","year":"2020","journal-title":"Nat. Rev. Mol. Cell Biol."},{"issue":"14","key":"2026081707161512100_cit36","doi-asserted-by":"publisher","first-page":"1419","DOI":"10.2217\/nnm-2019-0387","article-title":"Nanoparticles induce autophagy via mTOR pathway inhibition and reactive oxygen species generation","volume":"15","author":"Jia","year":"2020","journal-title":"Nanomedicine (Lond.)"},{"issue":"10-12","key":"2026081707161512100_cit37","doi-asserted-by":"publisher","first-page":"784","DOI":"10.1089\/ars.2020.8257","article-title":"Loop Between NLRP3 Inflammasome and Reactive Oxygen Species","volume":"36","author":"Dominic","year":"2022","journal-title":"Antioxid. Redox Signal."},{"issue":"10","key":"2026081707161512100_cit38","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2000915118","article-title":"Targeting tumor-derived NLRP3 reduces melanoma progression by limiting MDSCs expansion","volume":"118","author":"Tengesdal","year":"2021","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"issue":"4","key":"2026081707161512100_cit39","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1111\/jcpe.13258","article-title":"NLRP3 inflammasome mediates M1 macrophage polarization and IL-1\u03b2 production in inflammatory root resorption","volume":"47","author":"Zhang","year":"2020","journal-title":"J. Clin. Periodontol."}],"container-title":["ACS Applied Bio Materials"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsabm.6c00157","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/aabmcb\/article-pdf\/9\/16\/7312\/66354369\/mt-2026-00157a.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/aabmcb\/article-pdf\/9\/16\/7312\/66354369\/mt-2026-00157a.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T11:26:45Z","timestamp":1786966005000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/aabmcb\/article\/9\/16\/7312\/5238311\/Sustained-Release-GelMA-Quercetin-Hydrogel"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,1]]},"references-count":39,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2026,8,1]]},"published-print":{"date-parts":[[2026,8,17]]}},"URL":"https:\/\/doi.org\/10.1021\/acsabm.6c00157","relation":{},"ISSN":["2576-6422"],"issn-type":[{"value":"2576-6422","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,1]]}}}