Deciphering Molecular and Signaling Pathways of Extracellular Vesicles-Based Therapeutics for Alzheimer's Disease.

The rapidly growing aging population and increasing risk of Alzheimer's disease (AD) necessitate the development of more effective therapeutic strategies. Extracellular vesicles (EVs) have emerged as a promising therapeutic avenue for AD. EVs, including exosomes, microvesicles, and apoptotic bodies, are lipid bilayer-enclosed particles secreted by various cells that mediate intercellular communication through the transfer of proteins, lipids, RNA, and other bioactive molecules. EVs have various advantages over traditional therapeutic strategies, including high bioavailability, exceptional biocompatibility, and low immunogenicity. There are various methods for extraction and isolation of EVs to ensure reproducibility and characterization. Amyloid plaque formation, tau hyperphosphorylation, neuroinflammation, oxidative stress, and synaptic loss in AD are efficiently ameliorated using EVs. Moreover, signaling pathways are reported to be altered in AD, which have also been found to be regulated by EVs to promote neuronal growth and survival, including NFκB, MAPK, NLRP3, Nrf2/Keap1, HO-1, and TFAM. Preclinical studies have demonstrated that EVs derived from various sources, including mesenchymal stem cells (MSCs), neural stem cells (NSCs), and immune cells, can attenuate AD pathology by reducing amyloid-β (Aβ) accumulation, mitigating tau hyperphosphorylation, enhancing autophagy, and promoting synaptic plasticity. EV-based therapies for AD are in early clinical evaluation, with ongoing trials assessing their safety and efficacy. Key challenges include dosing, biodistribution, large-scale production, and immune responses. Despite these hurdles, EVs offer a promising, non-invasive alternative to stem cell therapy with lower risks and improved targeting potential.