Mesenchymal Stem Cell-Derived Exosomes for Alzheimer's Disease: Mechanisms, Preclinical Evidence, and Translational Challenges.

Alzheimer's disease (AD) is the leading cause of dementia and is driven by interacting pathological processes, including amyloid-β (Aβ) accumulation, tau hyperphosphorylation, neuroinflammation, and synaptic failure. Despite recent advances in anti-amyloid immunotherapy, disease-modifying benefits remain modest, highlighting the need for multitarget therapeutic strategies. Mesenchymal stem cell-derived exosomes (MSC-Exos) are nanoscale extracellular vesicles enriched with bioactive proteins, RNAs, and lipids that have been shown in experimental systems to cross the blood-brain barrier and modulate multiple AD-relevant pathways. This review synthesizes current evidence on MSC-Exo biology, cargo composition, and mechanisms of action in AD, critically evaluating their effects on Aβ clearance, tau pathology, neuroinflammation, and synaptic integrity across amyloid, tauopathy, and mixed pathology models. We further examine emerging clinical data on intranasal and intravenous MSC-Exo delivery, highlighting safety, feasibility, and early translational signals, while identifying key challenges that currently limit clinical advancement. These include incomplete understanding of biodistribution in the aging AD brain, the lack of mechanism-based potency assays, and uncertainty regarding direct anti-tau activity independent of amyloid modulation. By integrating preclinical, clinical, and translational perspectives, this review clarifies the current position of MSC-Exos in the AD therapeutic landscape and outlines priorities for future trials and biomarker-guided development. Importantly, this review explicitly distinguishes established evidence from mechanistic inference, particularly regarding tau-related effects, and frames MSC-Exos within a translational roadmap linking preclinical findings to key barriers in clinical development.