Sericin-based dual-module microspheres promote periodontal regeneration through four-dimensional microenvironment remodeling.

Periodontitis, a chronic inflammatory disease marked by oxidative stress, dysregulated inflammation, and alveolar bone resorption, remains a major oral health challenge due to conventional therapy's limited spatiotemporal control over tissue repair. To address this, we developed a sericin-based dual-module microsphere system (SeHA@EC): an inner pro-angiogenic/osteogenic module (ZnSr-Se-HA nanoparticles) and an outer anti-oxidant/anti-inflammatory module (EGCG-Ce Metal-phenolic networks, MPNs). The outer EGCG-Ce MPNs mitigate acute inflammation by scavenging ROS and modulating macrophage polarization toward M2, while the inner ZnSr-Se-HA module sequentially drives angiogenesis and osteogenesis during tissue repair. In vitro investigations demonstrated that SeHA@EC attenuated intracellular ROS levels, stabilized mitochondrial membrane potential, directed macrophage polarization toward the M2 phenotype via activating the SIRT1/FOXO3a/SOD-CAT axis and inhibiting NF-κB signaling, while additionally promoting angiogenesis and osteogenic differentiation of hPDLSCs. In vivo experiments further validated SeHA@EC's therapeutic efficacy in a rat periodontitis model: it significantly reduced intracellular ROS levels, suppressed pro-inflammatory cytokine expression (TNF-α, iNOS), upregulated anti-inflammatory marker expression (arginase, CD206), enhanced angiogenic and osteogenic activity, suppressed osteoclast activity, and accelerated alveolar bone regeneration. By overcoming the single-modal limitations of conventional biomaterials, this dual-module system establishes a microenvironment remodeling strategy for periodontal regeneration through spatiotemporal regulation of the pathological cascade.