fig1
Figure 1. MSC-EV-mediated modulation of neuroinflammation and stabilisation of the BBB. Schematic illustrates a mechanistic framework in which MSC-EVs modulate a coupled neuroinflammatory-neurovascular circuit that is commonly disrupted across neurodegenerative diseases. Following uptake by activated astrocytes and microglia, MSC-EV cargo suppresses key inflammatory signalling programmes (including NF-κB and MAPK), resulting in reduced production of pro-inflammatory cytokines and a shift toward a more homeostatic glial state[25]. This attenuation of glial reactivity limits NLRP3 inflammasome activation and inflammatory cell stress responses, thereby dampening self-reinforcing inflammatory loops within the CNS. In parallel, MSC-EVs act on the neurovascular compartment to stabilise CNS barrier architecture by preserving tight-junction organisation and reducing MMP2/9 activity[26,27]. Through coordinated actions on glial inflammatory output and vascular integrity, MSC-EVs interrupt pathogenic feedback between neuroinflammation and barrier dysfunction, positioning EV cargo as an active regulator of neuroimmune-vascular homeostasis. MSC-EV: Mesenchymal stem cell-derived extracellular vesicle; BBB: blood-brain barrier; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; MAPK: mitogen-activated protein kinase; NLRP3: NOD-like receptor family pyrin domain containing 3; CNS: central nervous system; MMP-2/9: matrix metalloproteinase 2/9; TLR4: Toll-like receptor 4; ZO-1: zonula occludens-1; TJP1: tight junction protein 1; STAT3: signal transducer and activator of transcription 3; IL-10: interleukin-10; IL-1β: interleukin-1 beta; TNF-α: tumour necrosis factor alpha; IL-6: interleukin-6; Aβ: amyloid-beta; USP15: ubiquitin-specific protease 15; NEK7: NIMA-related kinase 7; p38 MAPK: p38 mitogen-activated protein kinase; PI3K: phosphatidylinositol 3-kinase; AKT: protein kinase B; VEGF: vascular endothelial growth factor; Ang-1: angiopoietin-1; MAP3K8: mitogen-activated protein kinase kinase kinase 8; MK2: mitogen-activated protein kinase-activated protein kinase 2.
