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The cancer treatments linked to CTRCI include chemotherapy, hormone therapy, targeted therapy, and immunotherapy. Despite CTRCI severely affecting the psychological and social, cognitive functions, and the overall quality of life of cancer survivors, no effective medications are available currently. Our prior studies have indicated hippocampal tyrosine phosphatase protein tyrosine phosphatase receptor type O (PTPRO) as a putative target for CTRCI. However, phosphatase is historically considered undruggable, and delivering drugs across the blood\u2010brain barrier (BBB) is challenging. Here, we developed a novel delivery system using neuron\u2010targeted extracellular vesicles (EVs) engineered with a neuron\u2010specific peptide rabies virus glycoprotein (RVG) to transport a small activating RNA (saRNA) targeting\n                    <jats:italic>Ptpro<\/jats:italic>\n                    (RVG\u2010EVs\u2010sa\n                    <jats:italic>Ptpro<\/jats:italic>\n                    ). We evaluated the stability, dynamic distribution, cytotoxicity, and brain specificity of RVG\u2010EVs\u2010sa\n                    <jats:italic>Ptpro<\/jats:italic>\n                    in cellular and animal models. A single intravenous injection of RVG\u2010EVs\u2010sa\n                    <jats:italic>Ptpro<\/jats:italic>\n                    resulted in sustained elevation of PTPRO in the brain for at least 28 days in CTRCI mice. More importantly, RVG\u2010EVs\u2010sa\n                    <jats:italic>Ptpro<\/jats:italic>\n                    significantly alleviated CTRCI symptoms by enhancing neuronal survival, neurogenesis, and synaptic plasticity. These findings highlight the potential of RVG\u2010EVs\u2010sa\n                    <jats:italic>Ptpro<\/jats:italic>\n                    system for targeted treatment of CTRCI.\n                  <\/jats:p>","DOI":"10.1002\/advs.202520135","type":"journal-article","created":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T12:46:46Z","timestamp":1785242806000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mitigating Cancer Therapy\u2013Related Cognitive Impairment by Targeted Activation of Undruggable Phosphatase"],"prefix":"10.1002","volume":"13","author":[{"given":"Zhimeng","family":"Yao","sequence":"first","affiliation":[{"name":"Department of Urology Surgery The First Affiliated Hospital of Jinan University Jinan University  Guangzhou Guangdong China"},{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment Institute of Precision Cancer Medicine and Pathology School of Medicine Jinan University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhua","family":"Meng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment Institute of Precision Cancer Medicine and Pathology School of Medicine Jinan University  Guangzhou Guangdong China"},{"name":"Postdoctoral Research Station of Basic Medicine Jinan University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huanyi","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacy The First Affiliated Hospital of Jinan University Jinan University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinhui","family":"Jiang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment Institute of Precision Cancer Medicine and Pathology School of Medicine Jinan University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaona","family":"Lin","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment Institute of Precision Cancer Medicine and Pathology School of Medicine Jinan University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengyuan","family":"Hu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment Institute of Precision Cancer Medicine and Pathology School of Medicine Jinan University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pathology The First People's Hospital of Foshan  Foshan Guangdong 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shegan","family":"Gao","sequence":"additional","affiliation":[{"name":"College of Clinical Medicine Henan Key Laboratory of Cancer Epigenetics The First Affiliated Hospital of Henan University of Science and Technology  Luoyang Henan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weijing","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Pharmacy The First Affiliated Hospital of Jinan University Jinan University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianfan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Urology Surgery The First Affiliated Hospital of Jinan University Jinan University  Guangzhou Guangdong 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