Exosome-Based Carrier for RNA Delivery: Progress and Challenges

Abstract

In the last few decades, RNA-based drugs have emerged as a promising candidate to specifically target and modulate disease-relevant genes to cure genetic defects. The key to applying RNA therapy in clinical trials is developing safe and effective delivery systems. Exosomes have been exploited as a promising vehicle for drug delivery due to their nanoscale size, high stability, high biocompatibility, and low immunogenicity. We reviewed and summarized the progress in the strategy and application of exosome-mediated RNA therapy. The challenges of exosomes as a carrier for RNA drug delivery are also elucidated in this article. RNA molecules can be loaded into exosomes and then delivered to targeted cells or tissues via various biochemical or physical approaches. So far, exosome-mediated RNA therapy has shown potential in the treatment of cancer, central nervous system disorders, COVID-19, and other diseases. To further exploit the potential of exosomes for RNA delivery, more efforts should be made to overcome both technological and logistic problems.

Keywords: RNA loading; RNA therapy; challenges; drug delivery; exosomes; progress; targeting.

Figure 1

The biogenesis and cellular uptake modes of natural exosomes. During inward budding of the endosomal membrane, cargos are sorted into the forming vesicles through specific protein complex. By fusion of the MLVs with plasma membrane, exosomes are secreted into extracellular environment. Three ways of exosome cellular uptake: (1) endocytosis; (2) juxtacrine signaling; (3) Fusion.

Figure 2

Overview of exosome modification and targeted delivery. (A) Exosome modification methodologies. There are a number of approaches to modifying exosomes to achieve targeted delivery in practical applications. Exosomes can be engineered before they are isolated, by expressing fusion proteins on the exosomal surface (a). In addition, exosomes bearing functional groups, such as azides, can be produced by incubating the donor cells with azide-labeled metabolites (b). The azide-labeled exosomes can be further functionalized through either physical or chemical modification. Exogenous material can be introduced to exosomes by the endocytosis and exocytosis of the parent cells (c). Chemical installation of simple molecules can be achieved by direct reaction with amino acid side chains of exosomal membrane proteins (d). To install complicated molecules, azide groups are first introduced to the exosomal membrane. The cargos can be conjugated to dibenzobicyclooctyne (DBCO) and then introduced to the exosomal surface by strain-promoted azide-alkyne click reaction (SPAAC) (e). Physical modification can be applied by hydrophobic insertion (f) or fusion with liposomes (g). (B) Targeted strategies for modified exosomes. Engineered exosomes are guided to targeted cells through ligand-receptor-specific binding, magnetic force, pH gradient, and surface charge attraction.