Ultrabright ratiometric Raman-guided epilepsy surgery by intraoperatively visualizing proinflammatory microglia

  • Cell Rep Med. 2025 Jun 17;6(6):102155. doi: 10.1016/j.xcrm.2025.102155.
Cong Wang  1 ,  Zhi Li  2 ,  Xiao Zhu  3 ,  Wanbing Sun  4 ,  Yue Ding  5 ,  Wenjia Duan  6 ,  Difei Wang  7 ,  Yiqing Jiang  8 ,  Ming Chen  9 ,  Yuncan Chen  10 ,  Jiayi Hu  8 ,  Zheping Cai  11 ,  Jing Zhao  8 ,  Junfeng Wang  8 ,  Zhen Fan  9 ,  Faming Zheng  12 ,  Xingyu Zhou  13 ,  Fang Xie  14 ,  Jianping Zhang  15 ,  Yihui Guan  14 ,  Kui Yan  16 ,  Zuhai Lei  8 ,  Qinyue Wang  10 ,  Luting Wang  17 ,  Xiao Xiao  18 ,  Hairong Zheng  19 ,  Liang Chen  20 ,  Cong Li  21 ,  Ying Mao  22
Affiliations
  • 1. MOE Key Laboratory of Smart Drug Delivery, MOE Innovative Center for New Drug Development of Immune Inflammatory Diseases, School of Pharmacy, Zhongshan Hospital, Fudan University, Shanghai, China; Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Guangzhou, China; The Key Laboratory of Biomedical Imaging Science and System, Chinese Academy of Sciences, State Key Laboratory of Biomedical Imaging Science and System, Shenzhen 518055, China. Electronic address: [email protected].
  • 2. Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China; Department of Neurosurgery/Neuro-oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 3. Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fudan University, Shanghai, China.
  • 4. Department of Neurology and Research Center of Neurology in Second Affiliated Hospital and Key Laboratory of Medical Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China.
  • 5. Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 6. Academy of Forensic Science, Shanghai Key Laboratory of Forensic Medicine (21DZ2270800), Shanghai Key Laboratory of Forensic Medicine, Key Laboratory of Forensic Science, Ministry of Justice, 200063 Shanghai, China.
  • 7. Department of Neurosurgery, Kings College Hospital NHS Foundation Trust, Denmark Hill, London, UK.
  • 8. MOE Key Laboratory of Smart Drug Delivery, MOE Innovative Center for New Drug Development of Immune Inflammatory Diseases, School of Pharmacy, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 9. Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China.
  • 10. Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China.
  • 11. Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Ministry of Education, Behavioral and Cognitive Neuroscience Center, Institute of Science and Technology for Brain-Inspired Intelligence, Shanghai, China; State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai, China.
  • 12. State Key Laboratory of Transducer Technology, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai, China.
  • 13. Biomedical Engineering, Vanderbilt University, Nashville, TN, USA.
  • 14. PET Center, Huashan Hospital, Fudan University, Shanghai, China.
  • 15. Shanghai Engineering Research Center for Molecular Imaging Probes, Shanghai, China.
  • 16. Department of Chemistry, State Key Laboratory of Molecular Engineering of Polymers, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials and iChem, Fudan University, Shanghai, China.
  • 17. Shanghai Institute of Materia Medica Chinese Academy of Sciences, Shanghai, China.
  • 18. Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Ministry of Education, Behavioral and Cognitive Neuroscience Center, Institute of Science and Technology for Brain-Inspired Intelligence, Shanghai, China; State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai, China. Electronic address: [email protected].
  • 19. Paul C. Lauterbur Research Center for Biomedical Imaging, Institute of Biomedical and Health Engineering, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China. Electronic address: [email protected].
  • 20. Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China; State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai, China; Shanghai Key Lab of Brain Function Restoration and Neural Regeneration, Shanghai, China; Tianqiao and Chrissy Chen Institute for Translational Research, Shanghai, China. Electronic address: [email protected].
  • 21. MOE Key Laboratory of Smart Drug Delivery, MOE Innovative Center for New Drug Development of Immune Inflammatory Diseases, School of Pharmacy, Zhongshan Hospital, Fudan University, Shanghai, China; The Key Laboratory of Biomedical Imaging Science and System, Chinese Academy of Sciences, State Key Laboratory of Biomedical Imaging Science and System, Shenzhen 518055, China; State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai, China. Electronic address: [email protected].
  • 22. Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China; State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai, China; Shanghai Key Lab of Brain Function Restoration and Neural Regeneration, Shanghai, China. Electronic address: [email protected].
PMID: 40449482 DOI: 10.1016/j.xcrm.2025.102155
Abstract

Resective surgery is an effective approach for long-term seizure control in drug-resistant focal epilepsy when the epileptic focus (EF) can be accurately delineated and removed. However, intraoperative mapping of EF with electrocorticography is laborious, time-consuming, and highly vulnerable to the effects of anesthesia. Here, we demonstrated that activated microglia can be reliable biomarkers for EF localization. Leveraging a newly developed ratiometric Raman nanosensor, ultraHOCls, we successfully visualize proinflammatory microglia in live epileptic mice, allowing for precise EF delineation without the interference of anesthesia. Compared to electrocorticography-guided surgery, ultraHOCl-guided surgery results in a substantial 61% reduction in total seizure burden in epileptic mouse models. Notably, ultraHOCls sprayed on freshly excised human brain tissues can effectively discriminate epileptic regions from non-epileptic tissues with high sensitivity (94.89%) and specificity (93.3%). This work provides an alternative strategy for delineating the EF intraoperatively, potentially revolutionizing surgery outcomes in epilepsy patients.

Keywords
HOCl; Raman imaging; electrocorticography; epilepsy; microglia; myeloperoxidase; ratiometric; surgery.
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