A sequential sustained-release hydrogel with potent antimicrobial, anti-inflammatory, and osteogenesis-promoting properties for the treatment of periodontitis.

• Sequential release hydrogel caters to physiological healing process of periodontium. • The hydrogel can adapt to the complex therapeutic conditions within the oral cavity. • Sequential antibacterial, anti-inflammatory, and bone-promoting properties. • Timely degradability provides a supportive space for alveolar bone regeneration. Periodontitis is a pathological disorder characterized by inflammation and tissue destruction; it is primarily attributed to bacterial infection and immune responses. Nevertheless, existing strategies for drug delivery in periodontal treatment are insufficient to accommodate the intricate anatomical morphology of the periodontium and the complex oral environment. Furthermore, the disordered release of antibacterial agents and bone-promoting substances are not conducive to the natural healing of periodontal tissues, thus resulting in suboptimal therapeutic outcomes for periodontitis. In this study, we successfully co-loaded methylene blue (MB) and poly(lactic-co-glycolic acid) microspheres encapsulating Sema3A into a dopamine-grafted sodium alginate hydrogel (SA-DA). Experimental evidence indicates that MB/Sema3A@SA-DA exhibits favorable injectability, adhesion, and compression resistance characteristics, thus allowing it to adapt to the intricate therapeutic conditions of the oral cavity. The prompt release of MB (within 14 h) demonstrates its high antibacterial efficacy against periodontal pathogens upon exposure to 660 nm light, thereby establishing a microenvironment conducive to osteogenesis devoid of bacterial interference. Furthermore, the protracted release of Sema3A (within 28 d) shows noteworthy osteogenic capabilities and facilitates the polarization of macrophages toward the M2 phenotype. In a rat model of periodontitis, MB/Sema3A@SA-DA can be perfectly applied in situ to local periodontal lesions, and the sequential release of MB and Sema3A effectively achieved antibacterial, anti-inflammatory, and osteogenic effects. This therapeutic system avoids the abuse of antibiotics, surgical trauma, and repetitive administration. Hence, MB/Sema3A@SA-DA emerges as a safe, effective, minimally invasive, comfortable, and cost-effective treatment strategy with considerable potential for clinical implementation in periodontitis management. [ABSTRACT FROM AUTHOR]