Plant-derived extracellular vesicles in musculoskeletal disorders: a narrative review of mechanisms, therapeutic efficacy, and translational prospects

Musculoskeletal disorders (MSDs), including sarcopenia, osteoporosis, osteoarthritis, and rheumatoid arthritis, impose a growing global health burden, yet therapeutic options remain limited. Plant-derived extracellular vesicles (PDEVs), natural nanomedicines with multi-target potential, are emerging as promising candidates. This review examines preclinical evidence on PDEVs in MSDs, focusing on mechanisms, efficacy, and prospects. Preclinical studies indicate four interrelated mechanisms: gut microbiota remodeling, mitochondrial quality control, inflammation inhibition, and oxidative stress alleviation. PDEVs balance bone formation and resorption. In muscle, they preserve myofiber integrity via gut-muscle axis signaling, restore mitochondrial activity, and inhibit ubiquitin-proteasome-mediated degradation. In bone and joint, they promote osteoblast differentiation and chondrogenesis, suppress osteoclastogenesis, mitigate chondrocyte senescence, and inhibit synovial fibroblast activation. However, efficacy evidence remains limited because plant sources, isolation/characterization methods, models, doses, administration routes, and outcome assessments vary. Reporting of randomization, allocation concealment, blinding, sample-size calculation, and replication is often inadequate. Consequently, conclusions regarding PDEVs in MSDs remain hypothetical. Clinical translation requires standardized production, pharmacokinetic data, and long-term safety evaluation, as well as causal cross-species validation, multi-omics-based source screening, tissue-specific engineering, and rigorous trial validation.