The Biological Basis, Mechanisms of Action, and Optimization Strategies of Exosomes Derived from Mesenchymal Stem Cells for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is a complex neurodegenerative disorder whose pathological process involves multiple mechanisms, including Aβ deposition, tau protein abnormalities, neuroinflammation, synaptic damage, and neuronal loss. Current therapeutic approaches remain ineffective in halting disease progression; therefore, the development of multi-targeted, low-immunogenicity therapeutic strategies with efficient brain delivery is of great significance. Mesenchymal stem cell-derived exosomes (MSC-derived exosomes) inherit the immunomodulatory, neuroprotective, and tissue-repairing properties of MSCs, and possess good biocompatibility and the potential to cross the blood-brain barrier. Studies have shown that MSC-derived exosomes exert therapeutic effects by modulating neuroinflammation, promoting neurogenesis and synaptic plasticity, reducing Aβ deposition and tau pathology, and regulating multiple AD-related signaling pathways. At the same time, the molecular composition and functions of MSC-derived exosomes derived from different tissues exhibit heterogeneity, and their therapeutic efficacy is influenced by factors such as the source cells, culture conditions, preparation processes, and administration methods. In recent years, strategies such as engineered surface modification, functional molecule loading, three-dimensional culture, microenvironment pretreatment, large-scale production, as well as intranasal administration and biomaterial delivery systems have provided new directions for enhancing the brain-targeting ability, stability, yield, and therapeutic efficacy of MSC-derived exosomes. This review summarizes the biological basis of MSC-derived exosomes, their mechanisms of action in AD treatment, and optimization strategies, providing a reference for their further development and translational application as a cell-free therapeutic approach for AD.