A silk fibroin-based nanomodulator reshapes periodontal bone immunity by flipping the metabolic switch in macrophages to promote periodontal tissue regeneration.

Periodontitis involves chronic inflammation with dysfunctional macrophage metabolism. To address this, we uniquely combined the biological properties of silk fibroin with a desolvation method and biomineralization principles, developing a multifunctional nanocomposite termed SF-HA@TA-Mn. It was engineered to function as a nanomodulator of intracellular metabolism. This system utilizes TA for mitochondrial targeting and Mn ions for enhanced antioxidant activity, enabling precise scavenging of mtROS. By restoring mitochondrial homeostasis, the nanomodulator effectively reprograms macrophage metabolism, shifting polarization from a pro-inflammatory M1 to a reparative M2 phenotype, thereby remodeling the local immune microenvironment. Integrated multi-omics analyses revealed the nanomodulator primarily reprograms arginine metabolism by downregulating the JAK2-STAT1-ASS1 axis, while reversing inflammatory alterations in glutamine-fueled TCA cycle and purine metabolism. Additionally, it inhibits inflammatory damage in hPDLSCs and uses the osteoconductive property of SF-HA to synergistically couple immunomodulation with osteogenic differentiation. In vivo evaluation using a rat periodontitis model confirmed the dual efficacy of SF-HA@TA-Mn NPs, demonstrating significant anti-inflammatory effects and enhanced alveolar bone regeneration. By flipping the macrophage metabolic switch toward a reparative state, the nanomodulator effectively reverses the inflammatory oxidative stress cycle, actively promoting bone regeneration, and thereby offers a promising integrated therapeutic platform for periodontitis management.