Purpose: Fracture nonunion remains a major orthopaedic challenge, and dysregulation of the bone immune microenvironment is increasingly recognized as a key pathological driver. Methods: Single-cell RNA sequencing was performed on human nonunion tissues to characterize cellular heterogeneity. Network pharmacology and molecular docking analyses were used to identify potential therapeutic targets of Results: Single-cell RNA sequencing revealed M1 macrophage dominance and enhanced M1-mediated communication with osteoblasts and endothelial cells in nonunion tissues. The IL-17 signaling pathway and matrix metalloproteinase-3 were identified as key therapeutic targets. Isolated extracellular vesicles exhibited excellent biocompatibility, promoted M2 macrophage polarization, attenuated inflammation, and enhanced angiogenesis in vitro. In the rat fracture model, treatment with these extracellular vesicles significantly accelerated bone regeneration, as evidenced by increased bone bridging and callus formation. Conclusion: These findings establish a macrophage-centric pathological network in nonunion and demonstrate that