M2-Evs Reprogram Anxa1hi Neutrophils To Enhance Inflamed Bone Regeneration

Periodontitis is a microbiome-driven inflammatory disease that leads to irreversible alveolar bone loss and potential tooth loss. This study aimed to investigate the role of macrophage polarization in periodontal homeostasis and explore the therapeutic potential of M2 macrophage-derived extracellular vesicles (M2-EVs) in mitigating periodontitis-induced bone loss. A periodontitis mouse model was established using male C57BL/6 mice, and M2-EVs were administered to assess their impact on bone regeneration. Single-cell RNA sequencing was performed on periodontal tissues to analyze immune cell heterogeneity. The study was approved by the Ethics Committee of West China School of Stomatology. Single-cell RNA sequencing revealed a distinct Anxa1hi neutrophil subpopulation with pro-reparative properties following M2-EV treatment. This subpopulation exhibited osteogenic and angiogenic potential in vivo, mediated partly through oncostatin M (OSM) signaling. Further analysis suggested that M2-EVs modulated neutrophil maturation by upregulating key genes such as Acvrl1 and Fpr2, contributing to reparative neutrophil differentiation. These findings highlight the critical role of M2-EVs in reprogramming neutrophil function to support bone regeneration in periodontitis. Targeting M2 macrophage–neutrophil interactions may provide a promising therapeutic strategy for inflammatory bone loss.