期刊
ADVANCED MATERIALS
卷 31, 期 37, 页码 -出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/adma.201903277
关键词
active targeting; combinational RNAi; glioblastoma; ROS-responsive; siRNA delivery
类别
资金
- National Natural Science Foundation of China [NSFC 31600809, 31800841, U1604177, U1804139]
- National Key Technologies RAMP
- D Program of China [2018YFA0209800]
- Program of China's 1000-Talents Plan
- Key Research Program in Colleges and Universities of Henan Province [19zx006]
- Australian Endeavour Fellowship [69172018]
- Mason Foundation National Medical Program [MAS2017F034]
- National Health and Medical Research Council (NHMRC) Dementia Fellowship [APP1111611]
Small interfering RNA (siRNA) holds inherent advantages and great potential for treating refractory diseases. However, lack of suitable siRNA delivery systems that demonstrate excellent circulation stability and effective at-site delivery ability is currently impeding siRNA therapeutic performance. Here, a polymeric siRNA nanomedicine (3I-NM@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-NM@siRNA nanomedicine demonstrates effective at-site siRNA release resulting from tumoral reactive oxygen species (ROS)-triggered sequential destabilization. Furthermore, the utility of 3I-NM@siRNA for treating glioblastoma (GBM) by functionalizing 3I-NM@siRNA nanomedicine with angiopep-2 peptide is enhanced. The targeted Ang-3I-NM@siRNA exhibits superb blood-brain barrier penetration and potent tumor accumulation. Moreover, by cotargeting polo-like kinase 1 and vascular endothelial growth factor receptor-2, Ang-3I-NM@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-interaction stabilization together with inbuilt self-destruct 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.
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