Exosome-enabled bone defect repair: mechanistic foundations, bioengineered delivery, and artificial...

Bone defects remain a substantial clinical burden. Exosomes have been extensively investigated as cell-free therapeutic candidates, exhibiting favorable biocompatibility and potential applicability in bone defect repair. Mechanisms relevant to bone regeneration are delineated, including activation of osteogenic and angiogenic programs, modulation of osteoblast-osteoclast coupling, immune regulation, and extracellular matrix remodeling. Engineering strategies that enhance targeting, stability, and potency are summarized. Delivery platforms that provide spatial and temporal control of release at defect sites are also appraised. Artificial intelligence (AI) has been examined as an accelerator of translation. Applications include high‑fidelity exosome characterization, data‑driven biomaterial and formulation design, and prediction of therapeutic response from multimodal data. Large language models further assist evidence synthesis and hypothesis generation. Persistent barriers include heterogeneity in isolation and analytics, low yield and limited scalability, lack of standardization, and insufficient validation in disease‑relevant and large‑animal models. A forward agenda emphasizes standardized manufacturing and quality control, mechanism‑informed cargo and surface engineering, responsive delivery systems and AI‑enabled design-control pipelines to realize precise and reproducible exosome therapies for complex bone defects.