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.

通过被动脂质纳米颗粒和其他递送载体递送的一小部分短干扰 RNA (siRNA) 到达细胞的细胞质。因此，实现治疗效果所需的高剂量 siRNA 和递送载体可能会导致毒性。在这里，我们展示了将 siRNA 序列整合到一个基于 pre-miR-451 microRNA 的不依赖 Dicer 的 RNA 茎环中——该 microRNA 在许多细胞类型分泌的小细胞外囊泡中高度富集——降低了靶向基因的表达。 siRNA 在小鼠肝脏、肠道和肾小球中的 siRNA 剂量至少比通常通过脂质纳米颗粒递送的 siRNA 剂量低十倍。有效包装 siRNA 的小细胞外囊泡可以显着降低其治疗剂量。