Exosomes have been widely applied to the delivery of RNA and small molecules currently. However, the low targeting and specificity greatly limited the effect of exosome delivery. Here we designed an exosome that can perform the targeted delivery of two different types of RNA. Based on the mesenchymal stem cells (MSCs) derived exosomes, the RNA delivery system of targeted dendritic cells (DC‐Exosome) was constructed, using the layer by layer self‐assembly. DC‐Exosomes can specifically bind to DCs, while guiding the endocytosis of chimeras and exosome. Then aptamer/siRNA chimera was cut into mTOR siRNA by Dicer, and microRNA was released from exosome under lysosomal digestion. SIGN aptamer performed the rapid induction of immune tolerance, and later mTOR siRNA was formed to inhibit mTOR pathway and suppress immune responses. Exosomes could maintain long time‐stability after PEG‐PEI polyplexes modification and promote HLA‐G expression in DCs continuously. Animal experiments showed that DC‐Exosomes could induce immune tolerance at 3, 7, and 14 days after skin transplantation. Compared with the microRNA‐Exosome group, the number of CD11c+ DCs in DC‐Exosome group decreased, while the proportion of HLA‐G+ DCs increased remarkably. In conclusion, we constructed a new exosome‐based targeted delivery system which could effectively induce the immune tolerance in transplantation.

中文翻译：

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基于外泌体的靶向 RNA 递送用于皮肤移植中的免疫耐受诱导。

目前外泌体已广泛应用于RNA和小分子的递送。然而，低靶向性和特异性极大地限制了外泌体递送的效果。在这里，我们设计了一种外泌体，可以对两种不同类型的 RNA 进行靶向递送。基于间充质干细胞（MSCs）衍生的外泌体，利用逐层自组装构建了靶向树突细胞（DC-Exosome）的RNA递送系统。DC-Exosomes 可以与 DC 特异性结合，同时指导嵌合体和外泌体的内吞作用。然后将适配体/siRNA嵌合体通过Dicer切割成mTOR siRNA，通过溶酶体消化从外泌体中释放出microRNA。SIGN aptamer 进行了免疫耐受的快速诱导，随后形成了 mTOR siRNA 来抑制 mTOR 通路并抑制免疫反应。PEG-PEI 复合物修饰后外泌体可以保持长时间的稳定性，并持续促进 DC 中 HLA-G 的表达。动物实验表明，DC-Exosomes 可在皮肤移植后 3、7 和 14 天诱导免疫耐受。与 microRNA-Exosome 组相比，DC-Exosome 组中 CD11c+ DCs 的数量减少，而 HLA-G+ DCs 的比例显着增加。总之，我们构建了一种新的基于外泌体的靶向递送系统，可以有效地诱导移植中的免疫耐受。DC-Exosome 组中 CD11c+ DCs 的数量减少，而 HLA-G+ DCs 的比例显着增加。总之，我们构建了一种新的基于外泌体的靶向递送系统，可以有效地诱导移植中的免疫耐受。DC-Exosome 组中 CD11c+ DCs 的数量减少，而 HLA-G+ DCs 的比例显着增加。总之，我们构建了一种新的基于外泌体的靶向递送系统，可以有效地诱导移植中的免疫耐受。