Customized Hydrogel System for the Spatiotemporal Sequential Treatment of Periodontitis Propelled by ZEB1

Abstract Advanced periodontitis initiates with Porphyromonas gingivalis ( P. gingivalis ) infection, which subsequently triggers chronic inflammation, immune imbalance, and ultimately causes alveolar bone resorption. 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‐aluminum layered double hydroxide nanosheets (LDHs) loaded with icariin (ICA) are encapsulated into a gallic acid (GA)‐modified hydroxybutyl chitosan hydrogel (GA‐HBC), giving rise to a customized hydrogel system named GA‐HBC‐LIC, which can sequentially actualize antibacterial, anti‐inflammatory, and remineralization functions. A neutral chemical‐humoral 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‐box‐binding homeobox 1 (ZEB1) target of released zinc ions (Zn 2+ ) 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.