Available online 16 April 2025, 101312

The study is the first to report the therapeutic effects of QG-EVs on neuronal damage in CIRI.

This research reveals that QG-EVs upregulate the expression of transcription factor Atf4.

Based on scRNA-Seq analysis, this study identifies the crucial role of Atf4 in CIRI.

The study demonstrates that silencing Atf4 internally and externally inhibits the protection against CIRI mediated by QG-EVs.

This study provides new theoretical foundations and molecular targets for the diagnosis and treatment of CIRI.

Declaration of competing interest

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 regulatory 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 significantly 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.

Quercetin-3-O-β-D-glucuronic acid

Cerebral ischemia-reperfusion injury

Extracellular vesicles

Atf4

Neuroprotection

Oxidative stress

© 2025 The Author(s). Published by Elsevier B.V. on behalf of Xi’an Jiaotong University.