Efficient RNA delivery by integrin-targeted glutathione responsive polyethyleneimine capped gold nanorods
Efficient RNA delivery by integrin-targeted glutathione responsive polyethyleneimine capped gold nanorods
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DOI：
10.1016/j.actbio.2015.05.028
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发表时间：
2015-09-01
影响因子：
9.7
通讯作者：
Guo, Shengrong
中科院分区：
文献类型：
--
作者：
Wang, Feihu;Zhang, Wenjun;Guo, Shengrong
RNA干扰（RNAi）介导的基因沉默在基因治疗中具有重要的前景。有效RNAi的主要障碍是将治疗性RNA全身递送到细胞质中而不被捕获在细胞内的内体/溶酶体中。在此，我们报告了PEG化，RGD肽修饰，和二硫键交联的短聚乙烯亚胺（DSPEIs）功能化的金纳米棒（RDG）的靶向小发夹（SH）RNA递送的发展。RDG有效地将shRNA浓缩成稳定的纳米颗粒，允许通过α（v）β（3）整联蛋白介导的内吞作用高度特异性地靶向模型人脑癌细胞（U-87 MG-GFP）。内体逃逸（通过PEI的质子海绵效应）和通过高细胞内谷胱甘肽含量对二硫键交联的DSPEI的有效切割的组合效应触发了细胞质shRNA的快速释放，导致优异的RNAi效率和低细胞毒性。此外，通过PEG化提供的高稳定性和延长的血液循环允许载体的高度有效的靶向肿瘤积累和内化，从而在携带U-87 MG-GFP肿瘤的BALB/c小鼠中产生突出的肿瘤内基因沉默效率。结合被动和主动靶向、细胞内谷胱甘肽触发的“关-开”释放和内体逃逸的能力，本文开发的RDG纳米载体似乎是用于有效RNAi的非常有前途的非病毒载体。(C)2015 Acta Materialia Inc.由爱思唯尔有限公司出版。保留所有权利。
RNA interference (RNAi) mediated gene silencing holds significant promises in gene therapy. A major obstacle to efficient RNAi is the systemic delivery of the therapeutic RNAs into the cytoplasmon without being trapped in intracellular endo-/lyso-somes. Herein we report the development of a PEGylated, RGD peptide modified, and disulfide cross-linked short polyethylenimines (DSPEIs) functionalized gold nanorod (RDG) for targeted small hairpin (sh)RNA delivery. The RDG effectively condensed shRNAs into stable nanoparticles, allowing for highly specific targeting of model human brain cancer cells (U-87 MG-GFP) via the alpha(v)beta(3) integrins-mediated endocytosis. The combined effects of endosomal escape (via the proton-sponge effect of the PEIs) and efficient cleavage of the disulfide-cross-linked DSPEIs by the high intracellular glutathione content triggered rapid cytoplasma shRNAs release resulting in excellent RNAi efficiency and low cytotoxicity. Furthermore, the high stability and prolonged blood circulation afforded by PEGylation allowed for highly effective, targeted tumor accumulation and internalization of the carriers, resulting in outstanding intra-tumor gene silencing efficiency in U-87 MG-GFP tumor bearing BALB/c mice. Combining the capabilities of both passive and active targeting, intracellular glutathione-triggered "off-on" release and endosomal escape, the RDG nanocarrier developed herein appears to be a highly promising non-viral vector for efficient RNAi. (C) 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.