EXOSOME-MEDIATED TFEB DELIVERY ENHANCES AUTOPHAGY IN ALZHEIMER’S DISEASE

Impaired autophagy-lysosomal function is a central feature of Alzheimer’s disease (AD), driving amyloid accumulation, neuroinflammation, and progressive synaptic dysfunction. Transcription factor EB (TFEB), a key regulator of autophagy and lysosomal biogenesis, represents a promising target to restore proteostasis in AD. Here, we developed TFEB-loaded exosomes, including an exosome-based photo-inducible TFEB delivery system, to enable targeted and temporally controllable TFEB release. TFEB-loaded exosomes enhanced autophagy flux in PTF-LC3/SH-SY5Y cells, demonstrating increased RFP signals and activation of lysosomal pathways. In vivo, intranasally administered TFEB-loaded exosomes reduced amyloid plaque burden in both 5xFAD and ApoE4 hAPP knock-in mouse models. In the ApoE4 hAPP model, treatment decreased microglial colocalization with amyloid plaques, enhanced astrocytic responses, and attenuated neuroinflammatory markers, accompanied by partial improvements in memory performance. In the 5xFAD model, TFEB-exosome treatment induced molecular signatures consistent with autophagy activation, although cognitive improvements did not reach statistical significance, indicating model-specific differences in therapeutic responsiveness. Across both models, plaque reduction was robust and consistent, supporting autophagy-mediated clearance mechanisms. These findings demonstrate that TFEB-loaded exosomes effectively restore autophagic function and mitigate amyloid pathology, highlighting their potential as a therapeutic platform for AD. Further refinement of dosing, delivery route, and temporal control will be essential to maximize translational applicability and define optimal therapeutic windows.