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Edaravone, a free radical scavenger, is approved for the clinical treatment of ischemic stroke. However, edaravone directly decreases ROS even at low concentrations, which may inhibit the physiological effects of ROS and largely limit the clinical application of edaravone. To overcome this challenge, a ROS\u2010response nanoparticle system, edaravone\u2010loaded DEX\u2010CDIPBE (DEX\u2010CDIPBE\u2010ED), is developed for the selectively releasing edaravone in the ischemic penumbra during reperfusion, mitigating oxidative stress while minimizing off\u2010target effects. DEX\u2010CDIPBE\u2010ED produces potent antioxidant and neuroprotective effects in neuronal cells mimicking ischemic and\/or reperfusion phases of ischemic stroke. DEX\u2010CDIPBE\u2010ED further prevents behavioral deficits, reduces oxidative stress, and inhibites neuroinflammation with a higher potency than edaravone in the ischemic penumbra in middle cerebral artery occlusion\/reperfusion (MCAO\/R)\u2010treated rats. These findings highlight the potential of DEX\u2010CDIPBE\u2010ED as a pathological activated antioxidative therapy for ischemic stroke, offering enhanced neuroprotection and reduced systemic toxicity.<\/jats:p>","DOI":"10.1002\/adhm.202501962","type":"journal-article","created":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T02:24:43Z","timestamp":1751941483000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["ROS\u2010Response Nanoparticles for Edaravone Delivery: Pathological\u2010Activated Neuroprotection Against Ischemic\u2010Reperfusion Injury in Ischemic Stroke"],"prefix":"10.1002","volume":"14","author":[{"given":"Yi","family":"Zhou","sequence":"first","affiliation":[{"name":"Translational Medicine Center of Pain Emotion and Cognition Health Science Center Ningbo University  Zhejiang 315211 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengjiao","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Materials Science and Chemical Engineering Ningbo University  Zhejiang 315211 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutao","family":"Lin","sequence":"additional","affiliation":[{"name":"Translational Medicine Center of Pain Emotion and Cognition Health Science Center Ningbo University  Zhejiang 315211 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiyao","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Jiaxing Second Hospital  Jiaxing Zhejiang 314000 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yirui","family":"Hong","sequence":"additional","affiliation":[{"name":"Translational Medicine Center of Pain Emotion and Cognition Health Science Center Ningbo University  Zhejiang 315211 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sifang","family":"Zhao","sequence":"additional","affiliation":[{"name":"School of Materials Science and Chemical Engineering Ningbo University  Zhejiang 315211 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kangyang","family":"Gao","sequence":"additional","affiliation":[{"name":"Translational Medicine Center of Pain Emotion and Cognition Health Science Center Ningbo University  Zhejiang 315211 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongze","family":"Liang","sequence":"additional","affiliation":[{"name":"School of Materials Science and Chemical Engineering Ningbo University  Zhejiang 315211 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8645-4278","authenticated-orcid":false,"given":"Wei","family":"Cui","sequence":"additional","affiliation":[{"name":"Translational Medicine Center of Pain Emotion and Cognition Health Science Center Ningbo University  Zhejiang 315211 China"},{"name":"Department of Clinical Laboratory Jiaxing Second Hospital  Jiaxing Zhejiang 314000 China"},{"name":"Institute of One Health Science (IOHS) Ningbo University  Zhejiang 315211 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2577-3363","authenticated-orcid":false,"given":"Lingling","family":"Zhao","sequence":"additional","affiliation":[{"name":"School of Materials Science and Chemical Engineering Ningbo University  Zhejiang 315211 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,7,7]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1002\/adhm.202100455"},{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/adhm.202404268"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-023-03562-9"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2020.26867"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2021.4893"},{"key":"e_1_2_10_6_1","first-page":"2437","volume":"18","author":"Liu J.","year":"2019","journal-title":"Exp. 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