Reduction of the therapeutic dose of silencing RNA by packaging it in extracellular vesicles via a pre-microRNA backbone
Reduction of the therapeutic dose of silencing RNA by packaging it in extracellular vesicles via a pre-microRNA backbone
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DOI：
10.1038/s41551-019-0502-4
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发表时间：
2020-01-14
影响因子：
28.1
通讯作者：
Gibbings, Derrick
中科院分区：
文献类型：
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作者：
Reshke, Ryan;Taylor, James A.;Gibbings, Derrick
通过被动脂质纳米颗粒和其他递送载体递送的小百分比的短干扰RNA（siRNA）到达细胞的细胞质。因此，实现治疗结果所需的高剂量的siRNA和递送载体可能导致毒性。在这里，我们表明，将siRNA序列整合到基于pre-miR-451 microRNA的Dicer非依赖性RNA茎环中-它高度富集在许多细胞类型分泌的小细胞外囊泡中-降低了siRNA靶向的基因在小鼠肝，肠和肾小球中的表达，siRNA剂量至少比通常通过脂质纳米颗粒递送的siRNA剂量低10倍。将沉默RNA整合到高度富集于小细胞外囊泡中的microRNA的骨架中可以降低沉默RNA的治疗剂量。
A small percentage of the short interfering RNA (siRNA) delivered via passive lipid nanoparticles and other delivery vehicles reaches the cytoplasm of cells. The high doses of siRNA and delivery vehicle that are thus required to achieve therapeutic outcomes can lead to toxicity. Here, we show that the integration of siRNA sequences into a Dicer-independent RNA stem-loop based on pre-miR-451 microRNA-which is highly enriched in small extracellular vesicles secreted by many cell types-reduces the expression of the genes targeted by the siRNA in the liver, intestine and kidney glomeruli of mice at siRNA doses that are at least tenfold lower than the siRNA doses typically delivered via lipid nanoparticles. Small extracellular vesicles that efficiently package siRNA can significantly reduce its therapeutic dose.Integrating silencing RNA into the backbone of a microRNA that is highly enriched in small extracellular vesicles reduces the therapeutic dose of the silencing RNA.