Exosomes in Metabolic Bone Diseases: Regulators, Biomarkers and Targeted Delivery Systems

Background: Metabolic bone diseases represent prevalent global disorders characterized by disrupted bone homeostasis and chronic inflammation. This review utilizes a broad working definition encompassing osteoporosis and other classic metabolic bone disorders, including osteoarthritis, a primarily degenerative joint disease marked by significant metabolic-driven subchondral bone remodeling. Conventional diagnostic modalities prove inadequate for early-stage disease screening, while classical pharmacological interventions face limitations due to unsatisfactory targeting performance and severe long-term adverse reactions. An urgent clinical need persists for innovative diagnostic biomarkers and targeted therapeutic strategies. Exosomes, a sub-population of small extracellular vesicles (sEVs), are natural nanoscale intercellular vesicles derived from multivesicular bodies, playing critical regulatory roles in bone metabolism and offering substantial clinical translational potential. This review systematically elaborates the regulatory networks associated with exosomes, the biomarker potential of exosomal non-coding RNAs, and advanced engineering modifications for bone-targeted delivery in metabolic bone diseases. Methods: This narrative review involved a literature search conducted across PubMed, Web of Science, Scopus, and Embase from inception to December 2025, focusing on exosome biology, metabolic bone disorders, non-coding RNA biomarkers, and engineered bone-targeted delivery. Inclusion criteria encompassed peer-reviewed English original and review articles, while conference abstracts, case reports, editorials, and non-English literature were excluded. Eighty-two eligible studies underwent thematic analysis without a formal systematic search protocol or preregistration. Results: Exosomes orchestrate osteogenic and osteoclastogenic processes through established bone-metabolic signaling cascades. Exosomal microRNAs and circular RNAs demonstrate promising diagnostic performance in exploratory observational cohorts for early-stage screening and prognostic assessment of metabolic bone diseases; however, large-scale multi-center clinical validation remains insufficient. Engineered exosomes facilitate precise local bone intervention in preclinical animal models, overcoming significant drawbacks of conventional therapies in experimental settings. Nevertheless, clinical translation is obstructed by non-standardized production workflows and unresolved biosafety risks. Conclusions: Exosomes present promising dual diagnostic and therapeutic potential to enhance precision and individualized management of metabolic bone diseases. Further technical refinement in exosome preparation and modification will expedite orthopedic clinical translation and improve patient outcomes in metabolic bone disorders.