A Biomimetic Layered Silk Fibroin Microsphere Modulating Redox Homeostasis and Enhancing Osteogenic Differentiation for Synergistic Periodontal Regeneration
Yu Hu, Xuemin Ma, H Wan, Peirong Zhou, Y Chen, Hao Wang, Xia Wang, Junliang Chen, Rui Cai, Yun He, Gang Tao
Abstract
ABSTRACT Periodontitis‐associated alveolar bone loss results from a persistent inflammatory and oxidative microenvironment that impairs regenerative healing. To address this challenge, we developed a biomimetic, spatially stratified silk fibroin (SF)‐based microsphere system (Cu/Ce‐TA@HA‐SF) that restores redox homeostasis and serves as a bone filling material to support periodontal bone regeneration. The microsphere features a three‐layered architecture: a SF core produced via microfluidic technology ensures uniformity and adjustable mechanical properties, facilitating dynamic structural support during regeneration and adaptation to irregular defect sites. Surrounding the core, a hydroxyapatite (HA) layer enhances osteoconductivity, while the outer Cu 2+ /Ce 4+ –tannic acid (TA) nanozyme shell imparts antibacterial and reactive oxygen species (ROS)‐scavenging functionality. The nanozyme exhibits catalase CAT‐ and SOD‐like activities, effectively scavenging ROS, restoring mitochondrial function, and preserving human periodontal ligament stem cell (hPDLSC) viability. Notably, the microspheres inhibit ROS‐induced pyroptosis via suppression of the NLRP3/Caspase‐1/GSDMD signaling pathway. Concurrently, redox modulation regulates immune responses by activating Nrf2 and inhibiting NF‐κB signaling, thereby suppressing M1 macrophage polarization and enhancing M2 phenotypes. In vivo, Cu/Ce‐TA@HA‐SF microspheres achieved coordinated inflammation resolution, angiogenesis, and alveolar bone regeneration in a rat periodontitis model. This multifunctional, hierarchically engineered microsphere offers a promising strategy for redox‐driven immunomodulation and functional periodontal regeneration.