Carbon Monoxide Nanomodulator Reverses Ischemia‐Reperfusion Injury in Stroke: A Novel Dual‐Channel Therapy Mode of Co‐driving Neuroprotection and Neurogenesis

Abstract Recanalization intervention has improved patient outcomes in ischemic stroke, but severe ischemia‐reperfusion injury remains a major challenge, necessitating effective pharmacotherapy to reverse neuronal damage and recover neurofunctions. Traditional neuroprotection strategies aim to inhibit neuronal death, and are still insufficient to recover long‐term 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‐inflammation and anti‐oxidation. This reveals a new possibility to address the above challenge. Furthermore, this work develops a biomimetic and reactive oxygen species‐activated CO nanogenerator to effectively penetrate blood‐brain barrier, arrive in stroke‐affected regions, and release CO in a controlled manner for an innovative dual‐channel therapy strategy via co‐driving 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‐term neurological dysfunctions in ischemic stroke.