Targeting neuronal injury with intranasal Arc-engineered exosomes rescues cognitive deficits in Alzheimer's disease via the mTOR-autophagy pathway.

Abstract

The pathological complexity of Alzheimer's disease (AD) necessitates multifaceted therapeutic strategies. By integrating single-nucleus RNA sequencing analysis of 143,214 nuclei, this study identified excitatory neurons as the pivotal locus of cellular damage, manifesting significant dysregulation of pathways associated with proteostasis and autophagy. To counteract these cellular deficits, we developed a neuron-centric targeting strategy utilizing neural stem cell-derived exosomes engineered to overexpress the scaffolding protein Arc (Arc-exo). Following intranasal administration, Arc-exo demonstrated efficient central nervous system accumulation and achieved precision delivery by leveraging the intrinsic neurorestorative properties of the Arc protein and its specific affinity for neurons. Experimental results demonstrated that Arc-exo significantly alleviated AD pathological symptoms by reducing β-amyloid deposition, suppressing neuroinflammation, and repairing neuronal damage. Further mechanistic investigation revealed that Arc-exo restored cellular homeostasis by inhibiting the mTOR signaling pathway and reactivating autophagy. This study highlights engineered exosomes as efficient nanoplatforms for precision therapy in neurodegenerative diseases.