摘要This study investigates the neuroprotective potential of extracellular vesicles(EVs)delivering quercetin-3-O-β-D-glucuronic acid(QG-EVs)in cerebral ischemia-reperfusion injury(CIRI).Targeted brain delivery of QG-EVs was confirmed,with neuron cells identified as pivotal in modulating CIRI through single-cell RNA sequencing(scRNA-seq).Activating transcription factor 4(Atf4)was highlighted as a critical regu-latory factor,and in vitro studies revealed that silencing Atf4 diminished the neuroprotective effects of QG-EVs,increasing oxidative stress levels and neuronal apoptosis.In a CIRI mouse model,the knockdown of Atf4 attenuated the protective outcomes provided by QG-EVs,further affirming the role of Atf4 in mediating neuroprotection.Behavioral assessments and protein analysis showed that QG-EVs signifi-cantly reduced neuronal damage and pro-apoptotic markers,while improving neurological function via Atf4 upregulation.The outcomes hint at the potential of QG-EVs as a beneficial therapeutic modality to mitigate neuronal damage in CIRI by enhancing Atf4 expression,highlighting its potential for improving ischemic stroke outcomes.