Non-Bone-Derived Extracellular Vesicles in Osteoporosis: Evidence Mapping and Nanomedicine Translation.

BACKGROUND: Osteoporosis is influenced by signals from multiple tissues and body systems. Extracellular vesicles (EVs) and EV-like particles may contribute to bone remodeling, serve as biomarkers, or act as therapeutic delivery platforms, but these distinct research settings are often conflated and their evidential and translational maturity remains unclear. OBJECTIVE: To map research on non-bone-derived EVs and EV-like particles in osteoporosis-related bone remodeling using a purpose-based framework and to assess source and cargo attribution, evidence strength, and translational stage. METHODS: PubMed, Web of Science Core Collection, and EMBASE were searched from inception to July 15, 2026, supplemented by citation searching. Eligible original studies evaluated bone-related cellular or remodeling outcomes, clinically relevant bone phenotypes, biomarker associations, or therapeutic and delivery effects. Studies were classified as mechanism-, biomarker-, or intervention/delivery-focused, graded using an operational A-C evidence framework, and stratified from T0 to T3. RESULTS: We included 114 studies: 39 mechanism-focused, 22 biomarker-focused, and 53 intervention/delivery-focused. Most evidence remained preclinical, with 24 T0 and 76 T1 studies; 14 studies reached participant-level T2 evidence. Although 55 studies met level C criteria, EV dependence, cargo attribution, and endogenous source-to-bone attribution represented distinct and non-interchangeable dimensions, and strict in vivo source-to-bone attribution remained uncommon. In the bibliographic databases searched, no eligible published clinical or industrial evidence at T3 was identified. External validation of human biomarkers, biodistribution assessment, standardized potency assays, and product-level quality control were also uncommon. CONCLUSION: Non-bone-derived EVs and EV-like particles should be interpreted as a purpose-stratified evidence landscape rather than as a single biological mechanism. Current findings provide an evidence-organizing framework, not clinically ready diagnostic or therapeutic platforms. Priorities include stronger source tracing and cargo attribution, longitudinal human validation, quantitative biodistribution and potency assessment, and GMP-compatible product development.