Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes
Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes
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DOI：
10.1038/nbt.1807
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发表时间：
2011-04-01
影响因子：
46.9
通讯作者：
Wood, Matthew J. A.
中科院分区：
文献类型：
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作者：
Alvarez-Erviti, Lydia;Seow, Yiqi;Wood, Matthew J. A.
为了实现RNA药物的治疗潜力，必须开发有效的、组织特异性的和非免疫原性的递送技术。在这里，我们表明外泌体-转运RNA和蛋白质的内源性纳米囊泡（1，2）-可以将短干扰（si）RNA递送到小鼠的大脑。为了降低免疫原性，我们使用自衍生的树突状细胞用于外泌体生产。通过工程化树突细胞以表达与神经元特异性RVG肽融合的外泌体膜蛋白Lamp 2b来实现靶向（3）。通过电穿孔将纯化的外泌体加载有外源siRNA。脑内注射RVG靶向的外泌体将GAPDH siRNA特异性递送至脑中的神经元、小胶质细胞、少突胶质细胞，导致特异性基因敲低。预先暴露于RVG外来体不会减弱敲低，并且没有观察到其他组织中的非特异性摄取。在野生型小鼠中，外泌体介导的siRNA递送的治疗潜力通过BACE 1（阿尔茨海默病的治疗靶点）的强mRNA（60%）和蛋白质（62%）敲低来证明。
To realize the therapeutic potential of RNA drugs, efficient, tissue-specific and nonimmunogenic delivery technologies must be developed. Here we show that exosomes-endogenous nano-vesicles that transport RNAs and proteins(1,2)-can deliver short interfering (si) RNA to the brain in mice. To reduce immunogenicity, we used self-derived dendritic cells for exosome production. Targeting was achieved by engineering the dendritic cells to express Lamp2b, an exosomal membrane protein, fused to the neuron-specific RVG peptide(3). Purified exosomes were loaded with exogenous siRNA by electroporation. Intravenously injected RVG-targeted exosomes delivered GAPDH siRNA specifically to neurons, microglia, oligodendrocytes in the brain, resulting in a specific gene knockdown. Pre-exposure to RVG exosomes did not attenuate knockdown, and non-specific uptake in other tissues was not observed. The therapeutic potential of exosome-mediated siRNA delivery was demonstrated by the strong mRNA (60%) and protein (62%) knockdown of BACE1, a therapeutic target in Alzheimer's disease, in wild-type mice.