Abstract
Periodontitis treatment remains challenging due to the limitations of clinical medication therapies, including drug cytotoxicity, poor drug retention, immune imbalances, and epithelial barrier damage. Here, inspired by bioisosterism, we develop a dual-network hydrogel-based drug delivery system (M@PP) with materials structurally similar to minocycline (a commonly used medication). The M@PP hydrogel exhibits optimal mechanical strength and bioadhesion, ensuring sufficient drug retention inside periodontal pockets. The sustained release of minocycline, combined with the hydrogel's acidic microenvironment and the antioxidant functional groups, provides M@PP with excellent biocompatibility, potent antibacterial activity (98.1 % against P. gingivalis), and enhanced anti-inflammatory properties. In vivo studies demonstrate that M@PP regulates macrophage polarization, upregulates anti-inflammatory factors, and promotes the expression of epithelial junction-related cytokines. Additionally, M@PP activates pro-osteogenic mediators, with micro-CT analysis revealing increased trabecular bone density, thickness, and bone reconstruction. RNA sequencing further uncovers its therapeutic mechanisms, highlighting bacterial defense, immune modulation and pro-regenerative signaling. These combined benefits create a favorable immune microenvironment, facilitating epithelial barrier restoration and alveolar bone regeneration, achieving superior therapeutic outcomes compared to commercial products. This study presents a promising localized therapeutic strategy for periodontitis and biofilm-associated disorders.