Abstract
BackgroundEfficient and topical delivery of drugs is essential for maximized efficacy and minimized toxicity. In this study, we aimed to design an exosome-based drug delivery platform endowed with the ability of escaping from phagocytosis at non-target organs and controllably releasing drugs at targeted location.ResultsThe swtichable stealth coat CP05-TK-mPEG was synthesized and anchored onto exosomes through the interaction between peptide CP05 and exosomal surface marker CD63. Chlorin e6 (Ce6) was loaded into exosomes by direct incubation. Controllable removal of PEG could be achieved by breaking thioketal (TK) through reactive oxygen species (ROS), which was produced by Ce6 under ultrasound irradiation. The whole platform was called SmartExo. The stealth effects were analyzed in RAW264.7 cells and C57BL/6 mice via tracing the exosomes. To confirm the efficacy of the engineered smart exosomes, Bone morphogenetic protein 7 (Bmp7) mRNA was encapsulated into exosomes by transfection of overexpressing plasmid, followed by stealth coating, with the exosomes designated as SmartExo@Bmp7. Therapeutic advantages of SmartExo@Bmp7 were proved by targeted delivering Bmp7 mRNA to omental adipose tissue (OAT) of obese C57BL/6 mice for browning induction. SmartExo platform was successfully constructed without changing the basic characteristics of exosomes. The engineered exosomes effectively escaped from the phagocytosis by RAW264.7 and non-target organs. In addition, the SmartExo could be uptaken locally on-demand by ultrasound mediated removal of the stealth coat. Compared with control exosomes, SmartExo@Bmp7 effectively delivered Bmp7 mRNA into OAT upon ultrasound irradiation, and induced OAT browning, as evidenced by the histology of OAT and increased expression of uncoupling protein 1 (Ucp1).ConclusionsThe proposed SmartExo-based delivery platform, which minimizes side effects and maximizing drug efficacy, offers a novel safe and efficient approach for targeted drug delivery. As a proof, the SmartExo@Bmp7 induced local white adipose tissue browning, and it would be a promising strategy for anti-obesity therapy.Graphical
Highlights
Efficient and topical delivery of drugs is essential for maximized efficacy and minimized toxicity
Identification and characterization of exosomes CP05-TK-mPEG was anchored onto exosomes by direct incubation (Fig. 1A).To characterize CP05-TKmPEG functionalized exosomes (ExoCP05−TK−mPEG), morphology analysis through transmission electron microscope, particle size distribution analysis by dynamic light scattering and exosomal marker expression by western blot were applied
Evidence of Escaping from Phagocytosis of ExoCP05−TK− mPEG in vitro and in vivo In order to determine the ability of escaping from phagocytosis, Exo and ExoCP05−TK−mPEG were incubated with cells for different hours to observe the phagocytosis (Fig. 2A)
Summary
Efficient and topical delivery of drugs is essential for maximized efficacy and minimized toxicity. Despite the significant advantages in low immunogenicity, biocompatibility, ability of targeting different tissues with their surface ligands, etc., most of the exosomes have been found distributed into liver, spleen and other tissues with mononuclear phagocyte system (MPS), limiting their therapeutic efficacies [2,3,4,5,6]. Intensive efforts have focused on fusing targeting peptides and other moieties to exosomal surface to improve the delivering efficiency [7,8,9]. Those strategies are challenged as some targeting ligands are refractory to proper expression and prone to degradation [10]. To realize the controllable and targeting delivery of therapeutic molecules using exosomes as drug carriers, a smart enough exosome capable of escaping of MPS is urgently required
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