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Current neuroprotection and pharmaceutical approaches lack sufficient efficacy in restoring long-term neurological function. This study identifies carbon monoxide (CO) as an aneuromodulator that promotes neurogenesis through crosstalk between brain endothelial cells and neural stem cells, beyond anti-inflammatory and anti-oxidative effects. A biomimetic, ROS-activated CO nanogenerator targets the blood-brain barrier and releases CO in a controlled manner, enabling a dual-channel co-driving therapy of neuroprotection and neurogenesis. In a mouse ischemic stroke model, the strategy reverses brain injury and improves neurofunctional recovery, offering an advanced pharmacotherapy for long-term dysfunction.",{"@graph":69,"@context":123},[70,84,106],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/carbon-monoxide-nanomodulator-reverses-ischemia-reperfusion-injury-in-stroke-a-novel-dual-channel-therapy-mode-of-co-driving-neuroprotection-and-neurogenesis/439440/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/carbon-monoxide-nanomodulator-reverses-ischemia-reperfusion-injury-in-stroke-a-novel-dual-channel-therapy-mode-of-co-driving-neuroprotection-and-neurogenesis/439440.png","ImageObject",300,407,{"name":92,"@type":93},"Sarah ","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-03","2026-09-29",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",13,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"Why does ischemia-reperfusion injury remain a major challenge in ischemic stroke?","Question",{"text":113,"@type":114},"Recanalization restores blood supply but also triggers secondary damage to vulnerable neurons. The damage is mainly mediated by excessive oxidative stress and neuroinflammation, limiting long-term functional recovery.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"What new role does carbon monoxide (CO) play according to the study?",{"text":118,"@type":114},"CO is described as an aneuromodulator that promotes neurogenesis. The mechanism involves crosstalk between brain endothelial cells and neural stem cells, extending beyond established anti-inflammatory and anti-oxidation roles.",{"name":120,"@type":111,"acceptedAnswer":121},"How does the CO nanogenerator support the proposed dual-channel therapy?",{"text":122,"@type":114},"A biomimetic, ROS-activated CO nanogenerator is designed to penetrate the blood-brain barrier, reach stroke-affected regions, and release CO in a controlled manner. This enables simultaneous co-driving of neuroprotection and neurogenesis to reverse injury and recover neurofunctions.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},439440,1790702186,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":56,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145,"preview_page_count":4},962085320529,"https://ap-avatar.wpscdn.com/davatar_9964176cb1d06d4a9deccf72a44ae3dc","RESEARCH ARTICLE  \n[www.advancedscience.com](www.advancedscience.com)  \nCarbon Monoxide Nanomodulator Reverses Ischemia-Reperfusion Injury in Stroke: A Novel  \nDual-Channel Therapy Mode of Co-driving Neuroprotection and Neurogenesis  \nXuegang Niu, Bin Gao,* Hongyi Huang, Zesheng Li, Yibin Zhang, Quanlei Liu, Chao Zhang, Yang Dai, Jinkun Xu, Mingshan Liu, Yuanyuan Zhang, Yihe Wang, Penghu Wei, Yuanxiang Lin, Yongzhi Shan, Yumin Luo, Dezhi Kang,* and Guoguang Zhao*  \nRecanalization 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 aneuromodulator 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 toeffectively 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.  \n1. Introduction  \nIschemic stroke, resulting from cerebral artery occlusion and subsequent blood and oxygen depletion, is the most prevalent stroke subtype, accounting for >10 million new cases annually worldwide. [1–3] This has contributed to high mortality rates and long-term disability, posing a significant public health challenge. Current clinical therapies, i.e., intravenous thrombolysis and intra-arterial thrombectomy, aim to restore blood supply, but inevitably trigger the secondary damage to vulnerable neurons primarily mediated by excessive oxidative stress and neuroinflammation, referred to as ischemia-reperfusion injury.[4–6] Existing pharmaceutical interventions are hardly to modify the progression of ischemiareperfusion injury in clinical settings, and only acquire the limited efficacy. Therefore, advanced pharmacotherapy should be urgently explored to not only minimize brain  \nX. Niu, H. Huang, Z. Li, Q. Liu, C. Zhang, Y. Dai, J. Xu, M. Liu, Y. Zhang,  \nY. Wang, P. Wei, Y. Shan, G. Zhao Department of Neurosurgery Xuanwu Hospital  \nCapital Medical University Beijing 100053, China  \nE-mail: [ggzhao@ccmu.edu.cn](ggzhao@ccmu.edu.cn)  \nThe ORCID identification number(s) for the author(s) of this article  \ncan be found under [https://doi.org/10.1002/advs.202512333](https://doi.org/10.1002/advs.202512333)[ ](https://doi.org/10.1002/advs.202512333)© 2025 The Author(s). Advanced Science published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.  \nDOI: 10.1002/advs.202512333  \nX. Niu, B. Gao, Y. Zhang, Y. Lin, D. Kang  \nDepartment of Neurosurgery Neurosurgery Research Institute The First Affiliated Hospital Fujian Medical University Fuzhou 350005, China  \nE-mail: [gaobin11@tju.edu.cn](gaobin11@tju.edu.cn); [kangdezhi@fjmu.edu.cn](kangdezhi@fjmu.edu.cn)  \nX. Niu, B. Gao, Y. Lin, D. Kang  \nFujian Provincial Institutes of Brain Disorders and Brain Sciences The First Affiliated Hospital  \nFujian Medical University, Fuzhou Fujian 350005, China  \nY. Luo  \nBeijing Geriatric Medical Research Center Beijing 1000","cbCaibSDbeWtLLs6","https://ap.wps.com/l/cbCaibSDbeWtLLs6","pdf",15646175,"English","# Introduction\n## Ischemic stroke and ischemia-reperfusion injury\n## Limits of current therapies and drugs\n## CO as a neuromodulator and dual-channel concept\n# Neuroprotection and neurogenesis background\n## Neurogenesis and its failure after stroke\n## Need for strategies combining survival and neuron formation","[{\"question\":\"Why does ischemia-reperfusion injury remain a major challenge in ischemic stroke?\",\"answer\":\"Recanalization restores blood supply but also triggers secondary damage to vulnerable neurons. The damage is mainly mediated by excessive oxidative stress and neuroinflammation, limiting long-term functional recovery.\"},{\"question\":\"What new role does carbon monoxide (CO) play according to the study?\",\"answer\":\"CO is described as an aneuromodulator that promotes neurogenesis. The mechanism involves crosstalk between brain endothelial cells and neural stem cells, extending beyond established anti-inflammatory and anti-oxidation roles.\"},{\"question\":\"How does the CO nanogenerator support the proposed dual-channel therapy?\",\"answer\":\"A biomimetic, ROS-activated CO nanogenerator is designed to penetrate the blood-brain barrier, reach stroke-affected regions, and release CO in a controlled manner. This enables simultaneous co-driving of neuroprotection and neurogenesis to reverse injury and recover neurofunctions.\"}]","Carbon Monoxide Nanomodulator Reverses Ischemia-Reperfusion Injury in Stroke: A Novel Dual-Channel Therapy Mode of Co-driving Neuroprotection and Neurogenesis | PDF",1790688712,48]