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C-176 loaded Ce DNase nanoparticles synergistically inhibit the cGAS-STING pathway for ischemic stroke treatment

查看全文 作　　者：Zhixin [1,2]Zhu;Haipeng [2]Lu;Lulu [2]Jin;Yong [2]Gao;Zhefeng [2]Qian;Pan [1]Lu;Weijun [2]Tong;Pik Kwan [3]Lo;Zhengwei [2]Mao;Haifei [1]Shi 高影响力作者 机构地区：[1]Department of Orthopedics,1st Affiliated Hospital of Zhejiang University School of Medicine,Qingchun Road 79,Hangzhou,31000,China;[2]MOE Key Laboratory of Macromolecular Synthesis and Functionalization,Department of Polymer Science and Engineering,Zhejiang University,Hangzhou,310027,China;[3]Department of Chemistry and State Key Laboratory of Marine Pollution,City University of Hong Kong,Tat Chee Avenue,Kowloon,Hong Kong高影响力机构 出　　处：《Bioactive Materials》索引2023年第11期,共11页高影响力期刊 基　　金：the National Natural Science Foundation of China(No.22161132027,82272465,and 52273152);Zhejiang Provincial Natural Science Foundation of China(LY20H060008);the Starry Night Science Fund of Zhejiang University Shanghai Institute for Advanced Study(SN-ZJU-SIAS-006);‘Open Competition to Select the Best Candidates’Key Technology Program for Nucleic Acid Drugs of NCTIB(Grant No.NCTIB2022HS02006);Zhejiang High-Level Young Talent Special Support Plan for Dr.Zhengwei Mao. 摘　　要：The neuroinflammatory responses following ischemic stroke cause irreversible nerve cell death.Cell free-double strand DNA(dsDNA)segments from ischemic tissue debris are engulfed by microglia and sensed by their cyclic GMP-AMP synthase(cGAS),which triggers robust activation of the innate immune stimulator of interferon genes(STING)pathway and initiate the chronic inflammatory cascade.The decomposition of immunogenic dsDNA and inhibition of the innate immune STING are synergistic immunologic targets for ameliorating neuroinflammation.To combine the anti-inflammatory strategies of STING inhibition and dsDNA elimination,we constructed a DNase-mimetic artificial enzyme loaded with C-176.Nanoparticles are self-assembled by amphiphilic copolymers(P[CL35-b-(OEGMA20.7-co-NTAMA14.3)]),C-176,and Ce^(4+)which is coordinated with nitrilotriacetic acid(NTA)group to form corresponding catalytic structures.Our work developed a new nano-drug that balances the cGAS-STING axis to enhance the therapeutic impact of stroke by combining the DNase-memetic Ce^(4+)enzyme and STING inhibitor synergistically.In conclusion,it is a novel approach to modulating central nervus system(CNS)inflammatory signaling pathways and improving stroke prognosis. 关 键 词：Ischemic stroke Ce-based nano-nuclease The cGAS-STING signaling pathway Anti-inflammation
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