{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T08:58:12Z","timestamp":1790931492455,"version":"4.1.0"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T00:00:00Z","timestamp":1789948800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Biosci."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Periodontitis, a chronic inflammatory disorder driven by microbial dysbiosis and aberrant host immune responses, poses a significant challenge to periodontal tissue regeneration owing to persistent infection and impaired osteogenesis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Herein, we engineered an injectable hydrogel (denoted Cu@BG-HA) via borate ester crosslinking of copper-doped mesoporous bioactive glass nanoparticles (Cu@BG, 480 nm) with hyaluronic acid, aiming to concurrently address antibacterial, immunomodulatory, and osteogenic deficits in the periodontal microenvironment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The Cu@BG-HA hydrogel was synthesized through dynamic borate ester bond formation between Cu@BG nanoparticles and HA polymer networks. The physicochemical properties, ion release kinetics, and therapeutic efficacy were systematically characterized using\n                      <jats:italic>in vitro<\/jats:italic>\n                      models of bacterial infection, macrophage polarization, and osteoblast differentiation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The Cu@BG-HA hydrogel demonstrated sustained Cu\n                      <jats:sup>2+<\/jats:sup>\n                      release over 24 days, achieving eradication rates of 99.8% \u00b1 3.2% against\n                      <jats:italic>Staphylococcus aureus<\/jats:italic>\n                      and 98.6% \u00b1 1.7% against\n                      <jats:italic>Porphyromonas gingivalis<\/jats:italic>\n                      . Under lipopolysaccharide\/interferon-\u03b3 (LPS\/IFN-\u03b3) stimulation, the hydrogel effectively orchestrated macrophage phenotype switching from pro-inflammatory M1 toward anti-inflammatory M2 states in RAW264.7 cells. Furthermore, Cu@BG-HA markedly potentiated osteogenic differentiation of MC3T3-E1 pre-osteoblasts, evidenced by 1.8- and 1.7-fold enhancements in alkaline phosphatase activity and mineralized nodule formation, respectively, relative to control conditions.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Collectively, these findings establish Cu@BG-HA as a multifunctional, minimally invasive therapeutic platform that integrates potent antibacterial, immunomodulatory, and pro-osteogenic functionalities. This strategy offers substantial translational potential for periodontitis management and may be extendable to other inflammatory osteolytic pathologies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmolb.2026.1843490","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T11:16:34Z","timestamp":1789989394000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Immune-modulating copper-doped bioactive glass-based injectable hydrogel for periodontitis therapy"],"prefix":"10.3389","volume":"13","author":[{"given":"Huiqin","family":"lv","sequence":"first","affiliation":[{"name":"School of Stomatology, Jiangxi Medical College, Nanchang University","place":["Nanchang, China"]},{"name":"Jiangxi Provincial Key Laboratory of Oral Diseases","place":["Nanchang, China"]},{"name":"Jiangxi Provincial Clinical Research Center for Oral Diseases","place":["Nanchang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Onaza","family":"Ali","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Tu","sequence":"additional","affiliation":[{"name":"School of Stomatology, Jiangxi Medical College, Nanchang University","place":["Nanchang, China"]},{"name":"Jiangxi Provincial Key Laboratory of Oral Diseases","place":["Nanchang, China"]},{"name":"Jiangxi Provincial Clinical Research Center for Oral Diseases","place":["Nanchang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhe","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Stomatology, Jiangxi Medical College, Nanchang University","place":["Nanchang, China"]},{"name":"Jiangxi Provincial Key Laboratory of Oral Diseases","place":["Nanchang, China"]},{"name":"Jiangxi Provincial Clinical Research Center for Oral Diseases","place":["Nanchang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunyan","family":"Zhan","sequence":"additional","affiliation":[{"name":"School of Stomatology, Jiangxi Medical College, Nanchang University","place":["Nanchang, China"]},{"name":"Jiangxi Provincial Key Laboratory of Oral Diseases","place":["Nanchang, China"]},{"name":"Jiangxi Provincial Clinical Research Center for Oral Diseases","place":["Nanchang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"162985","DOI":"10.1016\/j.cej.2025.162985","article-title":"Cell sheet engineering platforms integrating antibacterial and thermo-responsive functionalities: Cu-nanoparticle-loaded P4VP brushes for retinal cell sheet harvesting","volume":"513","author":"Cie\u015blik","year":"2025","journal-title":"Chem. Eng. J."},{"key":"B2","doi-asserted-by":"publisher","first-page":"141","DOI":"10.3390\/app12010141","article-title":"Copper nanoparticles: synthesis and characterization, physiology, toxicity and antimicrobial applications","volume":"12","author":"Crisan","year":"2021","journal-title":"Appli. Sci."},{"key":"B3","doi-asserted-by":"publisher","first-page":"164153","DOI":"10.1016\/j.cej.2025.164153","article-title":"Prim-o-glucosylcimifugin-loaded nanodrug hydrogel alleviates periodontitis and colitis via modulating macrophage polarization and microbiota balance","volume":"518","author":"Ding","year":"2025","journal-title":"Chem. Eng. J."},{"key":"B4","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1016\/j.matlet.2017.12.075","article-title":"A simple way of modulating in vitro angiogenic response using cu and co-doped bioactive glasses","volume":"215","author":"Dziadek","year":"2018","journal-title":"Mater. Lett."},{"key":"B5","doi-asserted-by":"publisher","first-page":"3547","DOI":"10.1039\/D3BM00309D","article-title":"An ionic gel incorporating copper nanodots with antibacterial and antioxidant dual functions for deep tissue penetration treatment of periodontitis in rats","volume":"11","author":"Gao","year":"2023","journal-title":"Biomater. Sci."},{"key":"B6","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1016\/j.actbio.2025.10.058","article-title":"Inflammation-responsive biodegradable nanocomposite hydrogels for enhanced metalloimmunotherapy in chronic periodontitis","volume":"208","author":"Ge","year":"2025","journal-title":"Acta Biomater."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1402870","DOI":"10.3389\/fchem.2024.1402870","article-title":"Fabrication and characteristics of multifunctional hydrogel dressings using dopamine modified hyaluronic acid and phenylboronic acid modified chitosan","volume":"12","author":"Han","year":"2024","journal-title":"Front. Chem."},{"key":"B8","doi-asserted-by":"publisher","first-page":"125850","DOI":"10.1016\/j.ijpharm.2025.125850","article-title":"Revolutionizing periodontitis treatment: the promise of gelma hydrogel","volume":"681","author":"Hou","year":"2025","journal-title":"Int. J. Pharm."},{"key":"B9","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1039\/D3MH01563G","article-title":"A structural color hydrogel for diagnosis of halitosis and screening of periodontitis","volume":"11","author":"Hu","year":"","journal-title":"Mater. Horiz."},{"key":"B10","doi-asserted-by":"publisher","first-page":"3440","DOI":"10.1021\/acs.langmuir.3c02894","article-title":"Regulation of immune inflammation and promotion of periodontal bone regeneration by irisin-loaded bioactive glass nanoparticles","volume":"40","author":"Hu","year":"","journal-title":"Langmuir"},{"key":"B11","doi-asserted-by":"publisher","first-page":"6662","DOI":"10.1039\/d5bm00951k","article-title":"A plasma-derived fibrin in situ hydrogel for sustained release of copper and zinc ions in periodontitis treatment","volume":"13","author":"Huang","year":"2025","journal-title":"Biomater. Sci."},{"key":"B12","doi-asserted-by":"publisher","first-page":"7894","DOI":"10.1039\/D2NR06452A","article-title":"Facile engineering of resveratrol nanoparticles loaded with 20(s)-protopanaxadiol for the treatment of periodontitis by regulating the macrophage phenotype","volume":"15","author":"Huangfu","year":"2023","journal-title":"Nanoscale"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1389650","DOI":"10.3389\/fped.2024.1389650","article-title":"Inborn errors of immunity with susceptibility to S. aureus infections","volume":"12","author":"Kurz","year":"2024","journal-title":"Front. Pediatr."},{"key":"B14","doi-asserted-by":"publisher","first-page":"5091","DOI":"10.1016\/j.ceramint.2023.11.253","article-title":"Cu-doped bioactive glass with enhanced in vitro bioactivity and antibacterial properties","volume":"50","author":"Lallukka","year":"2024","journal-title":"Ceram. Int."},{"key":"B15","doi-asserted-by":"publisher","first-page":"2742","DOI":"10.1021\/acsbiomaterials.4c00220","article-title":"Advances in hydrogels for periodontitis treatment","volume":"10","author":"Li","year":"","journal-title":"ACS Biomater. Sci. Eng."},{"key":"B16","doi-asserted-by":"publisher","first-page":"17251","DOI":"10.1021\/acsnano.4c04816","article-title":"A double network composite hydrogel with self-regulating Cu2+\/luteolin release and mechanical modulation for enhanced wound healing","volume":"18","author":"Li","year":"","journal-title":"ACS Nano"},{"key":"B17","doi-asserted-by":"publisher","first-page":"7981","DOI":"10.1021\/acsnano.4c15227","article-title":"Bioactive zn\u2013v\u2013si\u2013ca glass nanoparticle hydrogel microneedles with antimicrobial and antioxidant properties for bone regeneration in diabetic periodontitis","volume":"19","author":"Li","year":"","journal-title":"ACS Nano"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1593545","DOI":"10.3389\/fbioe.2025.1593545","article-title":"Dual-functional titanium implants via polydopamine-mediated lithium and copper co-incorporation: synergistic enhancement of osseointegration and antibacterial efficacy","volume":"13","author":"Li","year":"","journal-title":"Front. Bioeng. Biotechnol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"174370","DOI":"10.1016\/j.cej.2026.174370","article-title":"Self-adaptive pro-healing hydrogel with material\u2013host antibacterial synergy and dynamic bio-adhesion","volume":"532","author":"Li","year":"2026","journal-title":"Chem. Eng. J."},{"key":"B20","doi-asserted-by":"publisher","first-page":"15538","DOI":"10.1021\/acs.jafc.3c02619","article-title":"Sulforaphene inhibits periodontitis through regulating macrophage polarization via upregulating dendritic cell immunoreceptor","volume":"71","author":"Liao","year":"2023","journal-title":"J. Agric. Food Chem."},{"key":"B21","doi-asserted-by":"publisher","first-page":"213158","DOI":"10.1016\/j.bioadv.2022.213158","article-title":"An injectable multifunctional thermo-sensitive chitosan-based hydrogel for periodontitis therapy","volume":"142","author":"Ma","year":"2022","journal-title":"Mater. Sci. Eng. C"},{"key":"B22","doi-asserted-by":"publisher","first-page":"2241","DOI":"10.3390\/pharmaceutics14102241","article-title":"Using copper-doped mesoporous bioactive glass nanospheres to impart anti-bacterial properties to dental composites","volume":"14","author":"Munir","year":"2022","journal-title":"Pharmaceutics"},{"key":"B23","doi-asserted-by":"publisher","first-page":"112522","DOI":"10.1016\/j.intimp.2024.112522","article-title":"Neural epidermal growth factor-like 1 protein (nell-1) alleviates periodontal tissue destruction in periodontitis by regulating the ratio of m2\/m1 macrophage phenotypes","volume":"137","author":"Ni","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"137893","DOI":"10.1016\/j.ijbiomac.2024.137893","article-title":"Hydrogel design and applications for periodontitis therapy: a review","volume":"284","author":"Pan","year":"","journal-title":"Int. J. Biol. Macromol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"23919","DOI":"10.1021\/acsnano.5c05266","article-title":"Metal-polyphenol network coated bilirubin nanoparticles for the alleviation of periodontitis via mild photothermal therapy and immunomodulatory therapy","volume":"19","author":"Pan","year":"","journal-title":"ACS Nano"},{"key":"B26","doi-asserted-by":"publisher","first-page":"128091","DOI":"10.1016\/j.ijbiomac.2023.128091","article-title":"Self-adaptable calcium-based bioactive phosphosilicate-infused gelatin-hyaluronic hydrogel for orthopedic regeneration","volume":"256","author":"Rethi","year":"2024","journal-title":"Int. J. Biol. Macromol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"123024","DOI":"10.1016\/j.biomaterials.2024.123024","article-title":"A nucleoside-based supramolecular hydrogel integrating localized self-delivery and immunomodulation for periodontitis treatment","volume":"316","author":"Shuai","year":"2025","journal-title":"Biomaterials"},{"key":"B28","doi-asserted-by":"publisher","first-page":"112547","DOI":"10.1016\/j.msec.2021.112547","article-title":"Investigation of topography effect on antibacterial properties and biocompatibility of nanohydroxyapatites activated with zinc and copper ions: in vitro study of colloids, hydrogel scaffolds and pellets","volume":"134","author":"Sobierajska","year":"2022","journal-title":"Mater. Sci. Eng. C"},{"key":"B29","doi-asserted-by":"publisher","first-page":"118780","DOI":"10.1016\/j.carbpol.2021.118780","article-title":"Injectable thiol-ene hydrogel of galactoglucomannan and cellulose nanocrystals in delivery of therapeutic inorganic ions with embedded bioactive glass nanoparticles","volume":"276","author":"Wang","year":"2022","journal-title":"Carbohydr. Polym."},{"key":"B30","doi-asserted-by":"publisher","first-page":"114688","DOI":"10.1016\/j.biopha.2023.114688","article-title":"Smart stimuli-responsive hydrogels for drug delivery in periodontitis treatment","volume":"162","author":"Wang","year":"2023","journal-title":"Biomed. Pharmacother."},{"key":"B31","doi-asserted-by":"publisher","first-page":"157660","DOI":"10.1016\/j.cej.2024.157660","article-title":"Ccl2-scavenging nanodecoy hydrogel multi-step remodel monocytes recruitment and macrophages polarization for periodontitis treatment","volume":"501","author":"Wang","year":"2024","journal-title":"Chem. Eng. J."},{"key":"B32","doi-asserted-by":"publisher","first-page":"800","DOI":"10.1038\/s41598-025-85123-x","article-title":"Preparation of ag-metal organic frameworks-loaded sodium alginate hydrogel for the treatment of periodontitis","volume":"15","author":"Wang","year":"","journal-title":"Sci. Rep."},{"key":"B33","doi-asserted-by":"publisher","first-page":"143205","DOI":"10.1016\/j.ijbiomac.2025.143205","article-title":"Injectable cus-loaded carboxymethyl and sulfonated chitosan hydrogel with antibacterial and self-healing properties promoting periodontal tissue regeneration","volume":"310","author":"Wang","year":"","journal-title":"Int. J. Biol. Macromol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"170187","DOI":"10.1016\/j.cej.2025.170187","article-title":"Nanohydrogel-mediated delivery of resolvin d1 for periodontitis therapy via immuno-osteogenic crosstalk modulation","volume":"526","author":"Wen","year":"2025","journal-title":"Chem. Eng. J."},{"key":"B35","doi-asserted-by":"publisher","first-page":"11342","DOI":"10.1021\/acsami.6b03100","article-title":"Europium-containing mesoporous bioactive glass scaffolds for stimulating in vitro and in vivo osteogenesis","volume":"8","author":"Wu","year":"2016","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"B36","doi-asserted-by":"publisher","first-page":"17912","DOI":"10.1039\/D1NR05198A","article-title":"An efficient treatment of biofilm-induced periodontitis using pt nanocluster catalysis","volume":"13","author":"Wu","year":"2021","journal-title":"Nanoscale"},{"key":"B37","doi-asserted-by":"publisher","first-page":"2403683","DOI":"10.1002\/adhm.202403683","article-title":"A microenvironment-responsive graphdiyne-iron nanozyme hydrogel with antibacterial and anti-inflammatory effect for periodontitis treatment","volume":"14","author":"Wu","year":"2025","journal-title":"Adv. Healthc. Mater."},{"key":"B38","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1016\/j.bioactmat.2025.02.015","article-title":"L-arginine modified mesoporous bioactive glass with ros scavenging and no release for periodontitis treatment","volume":"48","author":"Yao","year":"2025","journal-title":"Bioact. Mater."},{"key":"B39","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1016\/j.bioactmat.2025.09.030","article-title":"Thermosensitive antibacterial nanocomposite hydrogel guiding macrophage polarization and bone regeneration for periodontitis treatment","volume":"55","author":"Yu","year":"2026","journal-title":"Bioact. Mater."},{"key":"B40","doi-asserted-by":"publisher","first-page":"2000114","DOI":"10.1002\/adtp.202000114","article-title":"Self-reporting gold nanourchins for tumor-targeted chemo-photothermal therapy integrated with multimodal imaging","volume":"3","author":"Zhang","year":"2020","journal-title":"Adv. Ther."},{"key":"B41","doi-asserted-by":"publisher","first-page":"e09998","DOI":"10.1002\/advs.202509998","article-title":"Wang. Interfacial coordination-engineered emulgel modulates the osteo-immune microenvironment in periodontitis treatment via hif1 signaling pathway-induced metabolic reprogramming","volume":"12","author":"Zhang","year":"2025","journal-title":"Adv. Sci."},{"key":"B42","doi-asserted-by":"publisher","first-page":"7321","DOI":"10.1039\/D3TB00835E","article-title":"Advances in hydrogels for the treatment of periodontitis","volume":"11","author":"Zheng","year":"2023","journal-title":"J. Mater. Chem. B"},{"key":"B43","doi-asserted-by":"publisher","first-page":"3883","DOI":"10.1021\/acsbiomaterials.4c00107","article-title":"Gold nanoparticles confined in mesoporous bioactive glass for periodontitis therapy","volume":"10","author":"Zhou","year":"","journal-title":"ACS Biomater. Sci. Eng."},{"key":"B44","doi-asserted-by":"publisher","first-page":"150546","DOI":"10.1016\/j.cej.2024.150546","article-title":"Gold capped mesoporous bioactive glass guides bone regeneration via bmscs recruitment and drug adaptive release","volume":"487","author":"Zhou","year":"","journal-title":"Chem. Eng. J."},{"key":"B45","doi-asserted-by":"publisher","first-page":"123713","DOI":"10.1016\/j.biomaterials.2025.123713","article-title":"Nanotherapeutics for microenvironment modulation and immune homeostasis in periodontitis treatment","volume":"326","author":"Zhou","year":"2026","journal-title":"Biomaterials"}],"container-title":["Frontiers in Molecular Biosciences"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmolb.2026.1843490\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T08:48:23Z","timestamp":1790930903000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmolb.2026.1843490\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,21]]},"references-count":45,"alternative-id":["10.3389\/fmolb.2026.1843490"],"URL":"https:\/\/doi.org\/10.3389\/fmolb.2026.1843490","relation":{},"ISSN":["2296-889X"],"issn-type":[{"value":"2296-889X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,21]]},"article-number":"1843490"}}