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However, rtPA treatment can substantially increase blood\u2010brain barrier (BBB) permeability and susceptibility to hemorrhagic transformation. Herein, the mechanism underlying the side effects of rtPA treatment is investigated and demonstrated that ferroptosis plays an important role. The ferroptosis inhibitor, liproxstatin\u20101 (Lip) is proposed to alleviate the side effects. A well\u2010designed macrocyclic carrier, glucose\u2010modified azocalix[4]arene (GluAC4A), is prepared to deliver Lip to the ischemic site. GluAC4A bound tightly to Lip and markedly improved its solubility. Glucose, modified at the upper rim of GluAC4A, imparts BBB targeting to the drug delivery system owing to the presence of glucose transporter 1 on the BBB surface. The responsiveness of GluAC4A to hypoxia due to the presence of azo groups enabled the targeted release of Lip at the ischemic site. GluAC4A successfully improved drug accumulation in the brain, and Lip@GluAC4A significantly reduced ferroptosis, BBB leakage, and neurological deficits induced by rtPA in vivo. These findings deepen the understanding of the side effects of rtPA treatment and provide a novel strategy for their effective mitigation, which is of great significance for the treatment and prognosis of patients with ischemic stroke.<\/jats:p>","DOI":"10.1002\/advs.202309517","type":"journal-article","created":{"date-parts":[[2024,4,22]],"date-time":"2024-04-22T09:49:35Z","timestamp":1713779375000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Alleviating Recombinant Tissue Plasminogen Activator\u2010induced Hemorrhagic Transformation in Ischemic Stroke via Targeted Delivery of a Ferroptosis Inhibitor"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7969-1534","authenticated-orcid":false,"given":"Yan\u2010Qin","family":"Geng","sequence":"first","affiliation":[{"name":"School of Medicine Nankai University  Tianjin 300071 China"},{"name":"Tianjin Huanhu Hospital  Tianjin 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