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Traditional neuroprotection strategies aim to inhibit neuronal death, and are still insufficient to recover long\u2010term neurological dysfunctions. In this work, it is found that carbon monoxide (CO) as a neuromodulator exerts a new role in promoting neurogenesis via the crosstalk between brain endothelial cells and neural stem cells, which is beyond its recognized roles in anti\u2010inflammation and anti\u2010oxidation. This reveals a new possibility to address the above challenge. Furthermore, this work develops a biomimetic and reactive oxygen species\u2010activated CO nanogenerator to effectively penetrate blood\u2010brain barrier, arrive in stroke\u2010affected regions, and release CO in a controlled manner for an innovative dual\u2010channel therapy strategy via co\u2010driving neuroprotection and neurogenesis. This strategy further demonstrates its therapeutic effects on reversing brain injury and recovering neurofunctions in a mouse ischemic stroke model. This work reveals an important new role of CO, and further offers an advanced pharmacotherapy for long\u2010term neurological dysfunctions in ischemic stroke.<\/jats:p>","DOI":"10.1002\/advs.202512333","type":"journal-article","created":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T13:41:31Z","timestamp":1760708491000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Carbon Monoxide Nanomodulator Reverses Ischemia\u2010Reperfusion Injury in Stroke: A Novel Dual\u2010Channel Therapy Mode of Co\u2010driving Neuroprotection and Neurogenesis"],"prefix":"10.1002","volume":"13","author":[{"given":"Xuegang","family":"Niu","sequence":"first","affiliation":[{"name":"Department of Neurosurgery Xuanwu Hospital Capital Medical University  Beijing 100053 China"},{"name":"Department of Neurosurgery Neurosurgery Research Institute The First Affiliated Hospital Fujian Medical University  Fuzhou 350005 China"},{"name":"Fujian 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