Periodontitis is characterized by bacterial infection, elevated reactive oxygen species (ROS), excessive inflammation, and immune imbalance. Consequently, there is an urgent need to devise promising strategies capable of simultaneously combating infection, alleviating oxidative stress, suppressing inflammation, and regulating immunity in periodontitis management. Herein, an injectable silk fibroin/quercetin (SFQ) natural hydrogel was developed through self-assembly. The quercetin–silk fibroin interaction and the quercetin-enhanced β-sheet formed the self-assembled dual-network structure, bringing good injectability and mechanical stability. SFQ hydrogel with high biocompatibility promoted cell migration, scavenged ROS, relieved mitochondrial damage, and prevented cellular apoptosis. Meanwhile, SFQ hydrogel possessed a satisfactory anti-inflammatory ability and regulated immune response by inhibiting M1 polarization and promoting M2 polarization of macrophages. In addition, SFQ hydrogel can efficiently kill free bacteria and inhibit biofilm formation. In vivo experiments revealed that SFQ hydrogel significantly ameliorated inflammation, reduced collagen destruction, and regulated the immune micro milieu for tissue remodeling. Overall, self-assembled SFQ natural hydrogel offers a promising therapeutic option for improving the treatment of periodontitis.
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