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Traditional periodontal treatment focuses on the elimination of triggering factors, but tend to ignore the improvement of the inflammatory microenvironment and the remodeling of the osteogenic mineralization space. Herein, zinc\u2010aluminum layered double hydroxide nanosheets (LDHs) loaded with icariin (ICA) are encapsulated into a gallic acid (GA)\u2010modified hydroxybutyl chitosan hydrogel (GA\u2010HBC), giving rise to a customized hydrogel system named GA\u2010HBC\u2010LIC, which can sequentially actualize antibacterial, anti\u2010inflammatory, and remineralization functions. A neutral chemical\u2010humoral space is created for osteogenesis via means of sequential regulation by the smart hydrogel. Concomitantly, appropriate mechanical properties and degradation performance of the hydrogel provide a desirable physical space for remineralization. In the spatiotemporal modulation of the hydrogel, zinc finger E\u2010box\u2010binding homeobox 1 (ZEB1) target of released zinc ions (Zn\n                    <jats:sup>2+<\/jats:sup>\n                    ) action promotes macrophage polarization from M1 to M2 phenotype, thereby remodeling the immune microenvironment and releasing cytokines conducive to tissue regeneration. In sum, this study highlights the critical role of sequential inflammation regulation and the maintenance of osteogenic space in the regeneration of periodontal tissues, offering new insights for the clinical management of periodontitis.\n                  <\/jats:p>","DOI":"10.1002\/advs.202503338","type":"journal-article","created":{"date-parts":[[2025,4,5]],"date-time":"2025-04-05T14:52:19Z","timestamp":1743864739000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Customized Hydrogel System for the Spatiotemporal Sequential Treatment of Periodontitis Propelled by ZEB1"],"prefix":"10.1002","volume":"12","author":[{"given":"Jiafei","family":"Chen","sequence":"first","affiliation":[{"name":"The Affiliated Hospital of Stomatology School of Stomatology Zhejiang University of Medicine and Key Laboratory of Oral Biomedical Research of Zhejiang Province  Hangzhou 310006 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxu","family":"Guan","sequence":"additional","affiliation":[{"name":"The Affiliated Hospital of Stomatology School of Stomatology Zhejiang University of Medicine and Key Laboratory of Oral Biomedical Research of Zhejiang Province  Hangzhou 310006 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Cardiology Shaoxing Central Hospital  Shaoxing Zhejiang Province 312000 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingzhu","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology The First Affiliated Hospital Zhejiang University School of Medicine  Hangzhou 310003 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feiyu","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Silicon and Advanced Semiconductor Materials School of Materials Science and Engineering Zhejiang University  Hangzhou 310058 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Fang","sequence":"additional","affiliation":[{"name":"iBioMat PharmTeck (Hangzhou) Co. 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