Unveiling the Proteomic Landscape of Extracellular Vesicles: Implications for Neurodegeneration and Neuroprotection

ABSTRACT Extracellular vesicles (EVs) are instrumental mediators of intercellular communication and molecular exchange in neurodegenerative and neurovascular diseases. This review integrates recent advances in EV proteomics to elucidate their roles in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), traumatic brain injury (TBI), and ischemic stroke. Across these conditions, EVs carry disease‐relevant proteins that reflect and influence key pathological processes such as synaptic dysfunction, neuroinflammation, blood–brain barrier (BBB) disruption, and cell death. Proteomic profiling of brain‐ and biofluid‐derived EVs has uncovered specific biomarkers and signaling pathways, ranging from tau and α‐synuclein in AD and PD to mutant SOD1 in ALS and complement activation in stroke and TBI. Moreover, cell‐type‐specific EVs (e.g., from neurons, astrocytes, microglia, and stem cells) have been shown to exert either protective or deleterious effects, modulating apoptosis, axonal regeneration, and immune responses. Recent evidence highlights the translational potential of EVs as non‐invasive biomarkers and therapeutic vectors across multiple disorders. By mapping shared and divergent proteomic signatures in EVs, we review the mechanistic relevance and clinical utility of EVs in neurodegeneration and CNS injury. image