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<p>Ischemic stroke poses a severe threat to human health, and cerebral ischemia-reperfusion injury (CIRI) following recanalization remains a critical challenge for patient prognosis. This study investigated the role and mechanism of the circ_0017866/miR-124-3p/claudin domain containing 1 (CLDND1) axis in CIRI-induced endothelial-mesenchymal transition (EndMT) and evaluated the therapeutic potential of lipid nanoparticle (LNP)-encapsulated circ_0017866. Both oxygen-glucose deprivation/reperfusion cell and middle cerebral artery occlusion/reperfusion mouse models were established. Molecular interactions and gene/protein expression were validated using dual-luciferase reporter assays, quanti-tative real-time PCR, western blot, and immunofluorescence. In vitro, endothelial cell viability and function were assessed through CCK-8, Transwell migration, and tube formation assays. In vivo, LNP-mediated delivery of circ_0017866 was employed, and neurological deficits and cerebral infarct volume were evaluated using modified neu-rological severity scores and 2,3,5-triphenyltetrazolium chloride staining. Both in vivo and in vitro studies demonstrated that after ischemia-reperfusion, the expression of circ_0017866 and CLDND1 was downregulated, while miR-124-3p expression was upregulated. The dual-luciferase assay confirmed that miR-124-3p directly targets both circ_0017866 and CLDND1. In the OGD/R model, either circ_0017866 overexpression or miR-124-3p inhibition upregulated the expression of CLDND1 and occludin, downregulated α-smooth muscle actin (α-SMA) and Snail, and improved endothelial function. In the MCAO/R model, LNP-circ_0017866 treatment significantly improved neurological deficits, reduced infarct volume, and decreased the abnormal expression of EndMT-related markers. Circ_0017866 alleviates CIRI-induced EndMT by functioning as a molecular sponge for miR-124-3p to indirectly regulate CLDND1 expression. LNP-delivered circ_0017866 effectively mitigates neurological deficits and reduces cerebral infarct volume, providing a promising therapeutic strategy for ischemic stroke.</p>

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Lipid Nanoparticle-Delivered Circ_0017866 Alleviates Cerebral Ischemia-Reperfusion Injury by Suppressing Endothelial-Mesenchymal Transition via the miR-124-3p/CLDND1 Axis

  • 期刊论文

  • 发表日期：

    2026年5月23日

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  • Yuzhen Wang,
  • Yaozhuo Cai,
  • Xuan Zhang,
  • Dandan Wang,
  • Bailong Xin,
  • Xueli Cai,
  • Jingping Sun

摘要

Ischemic stroke poses a severe threat to human health, and cerebral ischemia-reperfusion injury (CIRI) following recanalization remains a critical challenge for patient prognosis. This study investigated the role and mechanism of the circ_0017866/miR-124-3p/claudin domain containing 1 (CLDND1) axis in CIRI-induced endothelial-mesenchymal transition (EndMT) and evaluated the therapeutic potential of lipid nanoparticle (LNP)-encapsulated circ_0017866. Both oxygen-glucose deprivation/reperfusion cell and middle cerebral artery occlusion/reperfusion mouse models were established. Molecular interactions and gene/protein expression were validated using dual-luciferase reporter assays, quanti-tative real-time PCR, western blot, and immunofluorescence. In vitro, endothelial cell viability and function were assessed through CCK-8, Transwell migration, and tube formation assays. In vivo, LNP-mediated delivery of circ_0017866 was employed, and neurological deficits and cerebral infarct volume were evaluated using modified neu-rological severity scores and 2,3,5-triphenyltetrazolium chloride staining. Both in vivo and in vitro studies demonstrated that after ischemia-reperfusion, the expression of circ_0017866 and CLDND1 was downregulated, while miR-124-3p expression was upregulated. The dual-luciferase assay confirmed that miR-124-3p directly targets both circ_0017866 and CLDND1. In the OGD/R model, either circ_0017866 overexpression or miR-124-3p inhibition upregulated the expression of CLDND1 and occludin, downregulated α-smooth muscle actin (α-SMA) and Snail, and improved endothelial function. In the MCAO/R model, LNP-circ_0017866 treatment significantly improved neurological deficits, reduced infarct volume, and decreased the abnormal expression of EndMT-related markers. Circ_0017866 alleviates CIRI-induced EndMT by functioning as a molecular sponge for miR-124-3p to indirectly regulate CLDND1 expression. LNP-delivered circ_0017866 effectively mitigates neurological deficits and reduces cerebral infarct volume, providing a promising therapeutic strategy for ischemic stroke.