Exosome‐based targeted RNA delivery for immune tolerance induction in skin transplantation

Abstract

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.

Research Progress in the Application of Exosomes in Immunotherapy

“…However, low targeting and specificity greatly limit the effectiveness of exosome delivery. Therefore, Li et al ( 74 ) designed an RNA delivery system based on MSC-derived exosomes capable of targeting specific binding of DCs and promoting HLA-G expression, where HLA-G can inhibit DC-triggered allogeneic T cell proliferation, thereby inducing long-term immune tolerance. Thus, exosomes of diverse origins can regulate DC differentiation, maturation, and function and may be important regulators of DC-induced immune responses.…”

Extracellular vesicle-based Nanotherapeutics: Emerging frontiers in anti-inflammatory therapy

“…A comprehensive review of aptamer-guided EV theranostics in oncology is available elsewhere 63 . With respect to inflammation targeting, a recent study successfully modified EVs with DNA aptamers against an adhesion receptor, ICAM-3 grabbing non-integrin (DC-SIGN), for the targeted delivery of therapeutic RNAs to dendritic cells 64 . However, being nucleic acid-based, degradation in biological media is the most significant challenge of aptamer-targeted systems.…”

Extracellular Vesicles as Potential Therapeutics for Inflammatory Diseases

“…MSCs derived exosomes was applied to the mTOR siRNA delivery system of targeting dendritic cells. Aptamer/siRNA chimera performed the targeted delivery of microRNAs into DCs and maintained long-term immune tolerance [ 132 ].…”