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

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.