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Curcumin (Cur) is a promising therapeutic agent, but its antioxidant activity is limited by low bioavailability and poor brain penetration. Herein, an intranasal delivery strategy using a tetrahedral framework nucleic acid (tFNAs)\u2013Cur nanoassembly (tFNAs\u2013Cur) was employed for CIRI treatment. tFNAs\u2013Cur was synthesized through self-assembly, achieving a high Cur loading efficiency of 87% and exhibiting potent scavenging activity against reactive oxygen species (ROS) including O2\u00b7\u2013, \u00b7OH, and H2O2. In vitro studies showed that tFNAs\u2013Cur inhibited oxygen glucose deprivation\/reoxygenation-induced ROS elevation of cytoplasm and mitochondria, and enhanced proliferation and migration of SH-SY5Y cells. In vivo studies demonstrated that intranasal administration of tFNAs\u2013Cur reduced cerebral infarct volume, enhanced neuronal survival, and improved neurological and behavioral outcomes in middle cerebral artery occlusion rats. Further mechanistic investigation using RNA sequencing revealed that tFNAs\u2013Cur exerted its effects by activating the Drd2\/\u03b2-arrestin2\/ERK signaling, thereby improving mitochondrial function and upregulating BDNF levels. Furthermore, hemolysis assays, serum biochemical measurements, and histopathological analyses demonstrated that tFNAs\u2013Cur possessed a favorable biosafety profile both ex vivo and in vivo. This study provides an intranasal antioxidant nanoassembly strategy for CIRI and holds potential for clinical translation.<\/jats:p>","DOI":"10.1021\/acsami.6c16346","type":"journal-article","created":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T20:02:11Z","timestamp":1792440131000},"page":"57264-57277","source":"Crossref","is-referenced-by-count":0,"title":["Intranasal Delivery of an Antioxidant Nanoassembly for Cerebral Ischemia-Reperfusion Injury via Drd2\/\u03b2-arrestin2\/ERK Signaling"],"prefix":"10.1021","volume":"18","author":[{"given":"Chen","family":"Li","sequence":"first","affiliation":[{"name":"Tianjin Medical University General Hospital , , ,","place":["Tianjin, China, 300052"]},{"name":"Tianjin Medical University General Hospital , , ,","place":["Tianjin, China, 300052"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zhao","sequence":"additional","affiliation":[{"name":"Tianjin Medical University General Hospital , , ,","place":["Tianjin, China, 300052"]},{"name":"Tianjin Medical University General Hospital , , ,","place":["Tianjin, China, 300052"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaofeng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Tianjin Medical University General Hospital , , ,","place":["Tianjin, China, 300052"]},{"name":"Tianjin Medical University General Hospital , , ,","place":["Tianjin, China, 300052"]},{"name":"Tianjin Medical University , , ,","place":["Tianjin, China, 300203"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiran","family":"Du","sequence":"additional","affiliation":[{"name":"Tianjin Medical University General Hospital , , ,","place":["Tianjin, China, 300052"]},{"name":"Tianjin Medical University General Hospital , , ,","place":["Tianjin, China, 300052"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaojiao","family":"Yu","sequence":"additional","affiliation":[{"name":"Tianjin Medical University , , ,","place":["Tianjin, China, 300203"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaomeng","family":"Yue","sequence":"additional","affiliation":[{"name":"Tianjin Medical University General Hospital , , ,","place":["Tianjin, China, 300052"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6136-9969","authenticated-orcid":true,"given":"Shao-Kai","family":"Sun","sequence":"additional","affiliation":[{"name":"Tianjin Medical University , , ,","place":["Tianjin, China, 300203"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0801-8435","authenticated-orcid":true,"given":"Ruxia","family":"Liu","sequence":"additional","affiliation":[{"name":"Tianjin Medical University , , ,","place":["Tianjin, China, 300203"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunxiao","family":"Wan","sequence":"additional","affiliation":[{"name":"Tianjin Medical University General Hospital , , ,","place":["Tianjin, China, 300052"]},{"name":"Tianjin Medical University General Hospital , , ,","place":["Tianjin, China, 300052"]},{"name":"Tianjin Medical University , , ,","place":["Tianjin, China, 300203"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,10,19]]},"reference":[{"key":"2026102802065544300_cit1","doi-asserted-by":"publisher","DOI":"10.1002\/mco2.70558","article-title":"Stroke: epidemiology, risk factors, signaling pathways, and clinical management","volume":"6","author":"Ren","year":"2025","journal-title":"MedComm"},{"key":"2026102802065544300_cit2","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1038\/s41392-022-01064-1","article-title":"Signaling pathways involved in ischemic stroke: molecular mechanisms and therapeutic interventions","volume":"7","author":"Qin","year":"2022","journal-title":"Signal Transduction Targeted Ther."},{"key":"2026102802065544300_cit3","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1016\/S0140-6736(16)30962-X","article-title":"Stroke","volume":"389","author":"Hankey","year":"2017","journal-title":"Lancet"},{"key":"2026102802065544300_cit4","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2025.103622","article-title":"Decoding ischemic stroke: perspectives on the endoplasmic reticulum, mitochondria, and their crosstalk","volume":"82","author":"Zhang","year":"2025","journal-title":"Redox Biol."},{"key":"2026102802065544300_cit5","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2025.102842","article-title":"Bidirectional regulation of neuronal autophagy in ischemic stroke: mechanisms and therapeutic potential","volume":"111","author":"Wu","year":"2025","journal-title":"Ageing Res. 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