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Lipid Nanoparticle-Delivered Circ_0017866 Alleviates Cerebral Ischemia-Reperfusion Injury by Suppressing
Yuzhen Wang1,2, Yaozhuo Cai1, Xuan Zhang1
1Department of Neurology, Lishui Central Hospital, The Fifth Affiliated Hospital of Wenzhou Medical University, 289 Kuocang Street, Lishui, 323000, Zhejiang Province, China.
Insights
This study reveals circ_0017866 alleviates cerebral ischemia-reperfusion injury (CIRI) by regulating the miR-124-3p/CLDND1 axis. Lipid nanoparticle delivery of circ_0017866 shows therapeutic potential for ischemic stroke.
Area of Science:
- Molecular Biology
- Neuroscience
- Biochemistry
Background:
- Cerebral ischemia-reperfusion injury (CIRI) is a significant challenge following ischemic stroke.
- Endothelial-mesenchymal transition (EndMT) plays a critical role in CIRI progression.
- Identifying novel therapeutic targets for CIRI is crucial.
Purpose of the Study:
- To investigate the role of the circ_0017866/miR-124-3p/CLDND1 axis in CIRI-induced EndMT.
- To evaluate the therapeutic efficacy of circ_0017866 delivered via lipid nanoparticles (LNPs) for CIRI.
Main Methods:
- Established oxygen-glucose deprivation/reperfusion (OGD/R) cell and middle cerebral artery occlusion/reperfusion (MCAO/R) mouse models.
- Utilized dual-luciferase reporter assays, qPCR, western blot, and immunofluorescence to analyze molecular interactions and expression.
- Assessed endothelial cell function in vitro and neurological deficits/infarct volume in vivo.
Main Results:
- Circ_0017866 and CLDND1 expression were downregulated, while miR-124-3p was upregulated in CIRI models.
- miR-124-3p was confirmed to target both circ_0017866 and CLDND1.
- Circ_0017866 overexpression or miR-124-3p inhibition improved endothelial function and reversed EndMT markers in vitro.
- LNP-mediated circ_0017866 delivery significantly improved neurological outcomes and reduced infarct volume in vivo.
Conclusions:
- Circ_0017866 acts as a molecular sponge for miR-124-3p, inhibiting EndMT and alleviating CIRI.
- LNP-delivered circ_0017866 demonstrates significant therapeutic potential for treating ischemic stroke and CIRI.
Abstract:
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.