Therapeutic mechanistic framework of mesenchymal stem cell-derived extracellular vesicles in neurodegenerative...

Neurodegenerative diseases are a spectrum of progressive disorders unified by chronic neuroinflammation, oxidative and mitochondrial stress, and accumulation of misfolded proteins that ultimately drive neuronal dysfunction and loss. Despite recurring convergence on these pathogenic processes, therapeutic progress has remained limited, underscoring the need for interventions capable of targeting convergent pathogenic pathways rather than single downstream features. Mesenchymal stromal/stem cells (MSCs) have emerged as promising therapeutic candidates through their paracrine actions that modulate inflammatory and cellular stress responses within the nervous system. Increasing evidence indicates that extracellular vesicles released by MSCs (MSC-EVs) are key mediators of these effects, transferring regulatory RNAs, lipids, and proteins that reprogram recipient cells, attenuate neuroinflammatory cascades, and support neuronal survival. MSC-EVs can recapitulate key therapeutic mechanisms of their parent cells and may offer potential advantages in safety, scalability, and delivery across the blood-brain barrier. While MSC-EVs are promising candidates for treating these diseases, the molecular mechanisms underlying their effects are still emerging. In this review, we synthesise evidence from experimental models to develop a mechanistic framework describing how MSC-EVs modulate interconnected regulatory modules that shape neuroinflammation with blood-brain barrier dysfunction, oxidative and mitochondrial stress, and dysregulated proteostasis with loss of neurotrophic support. We further discuss how this modular perspective may inform strategies to mitigate infection-associated neurodegenerative trajectories, with particular attention to post-SARS-CoV-2 neurological sequelae. By integrating these mechanistic insights, this review provides a conceptual foundation for the rational optimisation and bioengineering of MSC-EV-based therapies targeting convergent regulatory pathways in neurodegeneration.