Exosomes in Bone Generation and Repair: Focusing on Bone Microenvironmental Crosstalk and Engineering Biomaterial Designs.

The development of effective therapeutic strategies for bone regeneration and repair has proven to be highly challenging due to the sluggish and unpredictable nature of the healing process. Under pathological conditions, impaired cellular function can lead to poor biomineralization and compromised bone healing, resulting in various failures. Exosomes, as potent intercellular communicators capable of delivering diverse bioactive cargo, offer significant therapeutic promise. However, the lack of comprehensive understanding of their roles in the bone healing microenvironment and biomaterial design poses challenges for exosome-based therapies. This review provides the essential biological context for exosome application in bone regeneration, with a dual focus. First, we elucidate the pivotal roles of exosomes in mediating bone microenvironmental crosstalk, emphasizing their critical involvement in immunomodulation (eg, macrophage polarization), osteogenesis-angiogenesis coupling, osteoclast-osteoblast balance, neuro-skeletal communication, and dynamic extracellular matrix remodeling, rather than merely listing cell-specific functions. Second, building on this foundation, we summarize the rationale for engineering exosomal biomaterial designs. This includes strategies for exosome optimization (eg, targeting modifications, cargo loading, parental cell stimulation) and their integration with functional scaffolds to modulate the identified crosstalk pathways and create a conducive microenvironment. By delineating exosome functions within the bone microenvironmental network and outlining corresponding biomaterial engineering strategies, this review offers a holistic perspective essential for advancing exosome-based therapies.