M2 Macrophage‐Derived Extracellular Vesicles Reprogram Immature Neutrophils into Anxa1^hi Neutrophils to Enhance Inflamed Bone Regeneration

Periodontitis is a microbiome-related inflammation that can lead to irreversible bone reduction and even tooth loss. This study reveals that macrophage polarization states significantly influence periodontal homeostasis, with M2 macrophage-derived extracellular vesicles (M2-EVs) playing a pivotal role in mitigating periodontitis-induced bone loss. Single-cell RNA sequencing of periodontal tissues treated with M2-EVs uncovered a unique Anxa1^hi neutrophil subpopulation exhibiting pro-reparative properties. This subpopulation is characterized by immaturity and demonstrated osteogenic and angiogenic capabilities in vivo, partially mediated through the secretion of oncostatin M (OSM) signals. The findings suggest that this functional heterogeneity arises from M2-EVs disrupting the neutrophil maturation trajectory, with pivotal reprogramming genes, such as Acvrl1 and Fpr2, driving the differentiation of the Anxa1^hi reparative subpopulation. This work underscores the potential of targeting M2 macrophage-neutrophil interactions to promote the regeneration of inflamed bone tissues.