Exosome-amyloid interplay: Mechanisms, pathological roles, and materials-driven opportunities

Amyloid aggregation is a defining molecular feature of several neurodegenerative disorders, particularly Alzheimer's disease (AD), in which amyloid-β (Aβ) peptides assemble into heterogeneous oligomeric and fibrillar states. Extracellular vesicles (EVs) can interact with these assemblies, but their biological effects are context dependent: selected EV populations can sequester or promote clearance of toxic species, whereas other vesicles can support seeding, transport, or impaired clearance. This review adopts current EV terminology by reserving exosome for vesicles whose endosomal origin is demonstrated and using small EV (sEV) when biogenesis is not established. We critically examine the physicochemical determinants of EV-amyloid interactions, including membrane lipid composition, ceramide and cholesterol, cellular prion protein (PrPᶜ), Aβ isoform and assembly state, vesicle-to-Aβ ratio, recipient-cell competence, inflammation, and clearance capacity. We distinguish evidence from patient-cohort biomarker associations, mechanistic cell studies, animal-model causality, proof-of-concept engineering, and hypothesis-generating concepts. Patient studies reporting associations between circulating EV-associated Aβ42 and brain amyloid burden are discussed as promising but not yet sufficient to establish superiority over validated plasma biomarkers. Materials-enabled EV enrichment, microfluidics, surface-enhanced Raman spectroscopy, and engineered vesicle systems are evaluated alongside limitations in isolation, normalization, biodistribution, immunogenicity, manufacturing, and external clinical validation. This evidence-weighted framework positions EVs as context-sensitive components of proteinopathy and as investigational diagnostic or delivery platforms whose translation requires standardized characterization and independent validation.