Department of Vascular Surgery, Beijing Chao-yang Hospital, Capital Medical University, Beijing, China.
Department of Pathology, The 8th Medical Center of Chinese PLA General Hospital, Beijing, China.
J Biomed Mater Res A. 2020 May;108(7):1493-1500. doi: 10.1002/jbm.a.36919. Epub 2020 Mar 20.
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.
外泌体目前已广泛应用于 RNA 和小分子的递药系统中。然而，外泌体递送的靶向性和特异性低极大地限制了其效果。在这里，我们设计了一种能够靶向递送两种不同类型 RNA 的外泌体。基于间充质干细胞（MSCs）衍生的外泌体，通过层层自组装构建了靶向树突状细胞（DC-Exosome）的 RNA 递药系统。DC-Exosomes 可以特异性地与 DC 结合，同时引导嵌合体和外泌体的内吞作用。然后，适体/siRNA 嵌合体在 Dicer 的作用下被切割成 mTOR siRNA，而 miRNA 则在外体被溶酶体消化时从外体中释放出来。SIGN 适体迅速诱导免疫耐受，随后 mTOR siRNA 形成以抑制 mTOR 通路并抑制免疫反应。经 PEG-PEI 聚电解质复合物修饰后的外泌体具有长时间的稳定性，并能持续促进 DC 中 HLA-G 的表达。动物实验表明，在皮肤移植后 3、7 和 14 天，DC-Exosomes 可诱导免疫耐受。与 miRNA-Exosome 组相比，DC-Exosome 组中 CD11c+ DC 的数量减少，而 HLA-G+ DC 的比例显著增加。总之，我们构建了一种新的基于外泌体的靶向递药系统，可有效诱导移植中的免疫耐受。
