摘要Neuroinflammation and lysosomal dysfunction in microglia are increasingly recognized as critical pathological drivers of Alzheimer's disease,yet current anti-inflammatory or neuroprotective agents have limited brain delivery efficiency and cellular specificity.To address these challenges,this study proposes a novel nanotherapeutic paradigm based on extracellular nanovesicles(ENVs)for targeted modulation of microglial function.This research explored the potential of a novel nanotherapeutic platform involving ENVs functionalized with aptamers and encapsulating dexmedetomidine(Dex)to alleviate microglia-associated neuroinflammation in Alzheimer's disease.The effects on microglial lysosomal function,neuroinflammation,and cognitive performance were evaluated in an Alzheimer's disease mouse model.Cholesterol-conjugated PEG 2000 aptamers were used to modify extracellular nanovesicles derived from microglial cells.The nanovesicles(ZH-1c-ENVs)were loaded with Dex using ultrasound-assisted methods.Particle size,morphology,and drug release kinetics were characterized using dynamic light scattering and transmission electron microscopy.In vitro assays assessed microglial cell uptake and cytotoxicity,while in vivo biodistribution was evaluated in a mouse model.Proteomics,western blotting,quantitative reverse transcription-polymerase chain reaction,and immunofluorescence were employed to analyze the effects of ZH-1c-ENVs@Dex on microglial inflammation,lysosomal activity,and amyloid-beta clearance.Cognitive function improvements were assessed using the Morris water maze.ZH-1c-ENVs@Dex achieved efficient drug encapsulation and crossed the blood-brain barrier,delivering Dex selectively to microglial cells.Proteomic analysis revealed activation of the Sirtuin 3 signaling pathway,which reduced microglial inflammation and enhanced lysosomal function.These changes promoted amyloid-beta clearance in vitro and alleviated neuroinflammation in vivo.Treatment significantly improved cognitive performance in Alzheimer's disease mice.The ZH-1c-ENVs@Dex system represents a promising nanomedicine strategy for Alzheimer's disease therapy by modulating Sirtuin 3 activity,restoring microglial function,and improving cognitive outcomes.This study lays the groundwork for clinical translation of aptamer-modified ENVs as precision nanomedicines for neurodegenerative diseases.The ZH-1c-ENVs@Dex system integrates clinically safe components,efficiently traverses the blood-brain barrier,and selectively targets microglia,exhibiting remarkable potential for the treatment of Alzheimer's disease and related neurodegenerative disorders.This scalable and highly biocompatible nanovesicular platform offers a clinically translatable strategy with substantial therapeutic promise for neuroinflammatory and neurodegenerative diseases.