M2 Macrophage‐Derived Extracellular Vesicles Reprogram Immature Neutrophils into Anxa1hi Neutrophils to Enhance Inflamed Bone Regeneration

Abstract 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.