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However, lack of suitable siRNA delivery systems that demonstrate excellent circulation stability and effective at\u2010site delivery ability is currently impeding siRNA therapeutic performance. Here, a polymeric siRNA nanomedicine (3I\u2010NM@siRNA) stabilized by triple interactions (electrostatic, hydrogen bond, and hydrophobic) is constructed. Incorporating extra hydrogen and hydrophobic interactions significantly improves the physiological stability compared to an siRNA nanomedicine analog that solely relies on the electrostatic interaction for stability. The developed 3I\u2010NM@siRNA nanomedicine demonstrates effective at\u2010site siRNA release resulting from tumoral reactive oxygen species (ROS)\u2010triggered sequential destabilization. Furthermore, the utility of 3I\u2010NM@siRNA for treating glioblastoma (GBM) by functionalizing 3I\u2010NM@siRNA nanomedicine with angiopep\u20102 peptide is enhanced. The targeted Ang\u20103I\u2010NM@siRNA exhibits superb blood\u2013brain barrier penetration and potent tumor accumulation. Moreover, by cotargeting polo\u2010like kinase 1 and vascular endothelial growth factor receptor\u20102, Ang\u20103I\u2010NM@siRNA shows effective suppression of tumor growth and significantly improved survival time of nude mice bearing orthotopic GBM brain tumors. New siRNA nanomedicines featuring triple\u2010interaction stabilization together with inbuilt self\u2010destruct delivery ability provide a robust and potent platform for targeted GBM siRNA therapy, which may have utility for RNA interference therapy of other tumors or brain diseases.<\/jats:p>","DOI":"10.1002\/adma.201903277","type":"journal-article","created":{"date-parts":[[2019,7,26]],"date-time":"2019-07-26T09:12:58Z","timestamp":1564132378000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":205,"title":["ROS\u2010Responsive Polymeric siRNA Nanomedicine Stabilized by Triple Interactions for the Robust Glioblastoma Combinational RNAi Therapy"],"prefix":"10.1002","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2932-1062","authenticated-orcid":false,"given":"Meng","family":"Zheng","sequence":"first","affiliation":[{"name":"Henan\u2010Macquarie University Joint Centre for Biomedical Innovation School of Life Sciences Henan University  Kaifeng Henan 475004 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Liu","sequence":"additional","affiliation":[{"name":"Henan\u2010Macquarie University Joint Centre for Biomedical Innovation School of Life Sciences Henan University  Kaifeng Henan 475004 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yibin","family":"Wang","sequence":"additional","affiliation":[{"name":"Henan\u2010Macquarie University Joint Centre for Biomedical Innovation School of Life Sciences Henan University  Kaifeng Henan 475004 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongya","family":"Zhang","sequence":"additional","affiliation":[{"name":"Henan\u2010Macquarie University Joint Centre for Biomedical Innovation School of Life Sciences Henan University  Kaifeng Henan 475004 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Zou","sequence":"additional","affiliation":[{"name":"Henan\u2010Macquarie University Joint Centre for Biomedical Innovation School of Life Sciences Henan University  Kaifeng Henan 475004 China"},{"name":"Department of Biomedical Sciences Faculty of Medicine and Health Sciences Macquarie University  Sydney NSW 2109 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weimin","family":"Ruan","sequence":"additional","affiliation":[{"name":"Henan\u2010Macquarie University Joint Centre for Biomedical Innovation School of Life Sciences Henan University  Kaifeng Henan 475004 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinlong","family":"Yin","sequence":"additional","affiliation":[{"name":"Henan\u2010Macquarie University Joint Centre for Biomedical Innovation School of Life Sciences Henan University  Kaifeng Henan 475004 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Tao","sequence":"additional","affiliation":[{"name":"Center for Nanomedicine and Department of Anesthesiology Brigham and Women's Hospital Harvard Medical School  Boston MA 02115 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jong Bae","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Cancer Biomedical Science Graduate School of Cancer Science and Policy National Cancer Center  Goyang 10408 South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingyang","family":"Shi","sequence":"additional","affiliation":[{"name":"Henan\u2010Macquarie University Joint Centre for Biomedical Innovation School of Life Sciences Henan University  Kaifeng Henan 475004 China"},{"name":"Department of Biomedical Sciences Faculty of Medicine and Health Sciences Macquarie University  Sydney NSW 2109 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,7,26]]},"reference":[{"key":"e_1_2_4_1_1","volume-title":"Alzheimer Disease Overview","author":"Bird T. 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