Macrophage-derived exosomes in bone tissue regeneration: spatiotemporal immunomodulation, engineering advances, and translational frontiers

Abstract Background Bone regeneration unfolds through sequential inflammatory, reparative, and remodeling phases, with macrophages functioning as pivotal regulators across these stages. Accumulating evidence identifies macrophage-derived exosomes (M-Exos) as key mediators of intercellular communication that dynamically shape the bone healing microenvironment. Main body This review synthesizes current evidence on the spatiotemporal roles of M-Exos during bone healing and discusses how donor macrophage states may shape vesicle function across inflammatory, reparative, and remodeling phases. The discussion elucidates how dynamic macrophage functional states shape exosomal cargo and biological activity during distinct stages of repair. Concurrently, emerging engineering strategies to harness and enhance M-Exos’ regenerative functions are evaluated, including exosome engineering, therapeutic cargo optimization, and biomaterial-assisted delivery approaches. In addition, this paper scrutinizes the translational landscape of M-Exos, emphasizing their potential as a cell-free therapeutic modality for bone tissue engineering while outlining key challenges critical for clinical implementation. Conclusions By integrating the spatiotemporal functions of macrophage-derived exosomes (M-Exos) and single-cell-resolved landscapes of macrophage functional states, this review delineates the mechanistic links among macrophage state transitions, M-Exo cargo profiles, and regenerative outcomes across distinct phases of bone healing. It further provides a theoretical basis for developing stage-adaptive and functionally tunable M-Exo–based strategies for bone regeneration.