A review on exosomes application in clinical trials: perspective, questions, and challenges

Abstract

Background: Exosomes are progressively known as significant mediators of cell-to-cell communication. They convey active biomolecules to target cells and have vital functions in several physiological and pathological processes, and show substantial promise as novel treatment strategies for diseases.

Methods: In this review study, we studied numerous articles over the past two decades published on application of exosomes in different diseases as well as on perspective and challenges in this field.

Results: The main clinical application of exosomes are using them as a biomarker, cell-free therapeutic agents, drug delivery carriers, basic analysis for exosome kinetics, and cancer vaccine. Different exosomes from human or plant sources are utilized in various clinical trials. Most researchers used exosomes from the circulatory system for biomarker experiments. Mesenchymal stem cells (MSCs) and dendritic cells (DCs) are two widely held cell sources for exosome use. MSCs-derived exosomes are commonly used for inflammation treatment and drug delivery, while DCs-exosomes are used to induce inflammation response in cancer patients. However, the clinical application of exosomes faces various questions and challenges. In addition, translation of exosome-based clinical trials is required to conform to specific good manufacturing practices (GMP). In this review, we summarize exosomes in the clinical trials according to the type of application and disease. We also address the main questions and challenges regarding exosome kinetics and clinical applications.

Conclusions: Exosomes are promising platforms for treatment of many diseases in clinical trials. This exciting field is developing hastily, understanding of the underlying mechanisms that direct the various observed roles of exosomes remains far from complete and needs further multidisciplinary research in working with these small vesicles. Video Abstract.

Keywords: Clinical trials; Exosome therapy; Exosomes; Extracellular vesicles.

Fig. 1

Extracellular vesicles (EVs) biogenesis. Two main subclasses of EVs are exosomes and microvesicles (MVs). Exosomes biogenesis is complex and occurs inside multivesicular bodies (MVBs) located in the cytoplasm. ESCRT complexes and different molecules contribute to loading, sorting and forming exosomes in ATP dependent and independent manners. Exosomes cargo come from Golgi apparatus, the endosomal pathway, and the cytoplasm. Rab proteins mediate intracellular trafficking of endosomal compartments and exosomes. MVBs have been reported to fuse with either plasma membrane, lysosomes or amphisoms. When MVBs fuse with the plasma membrane, exosomes are released into the extracellular milieu. There is evidence that exosomes biogenesis pathway may crosstalk with autophagy flux. MVBs may fuse with autophagosomes and form the hybrid vesicles known ‘’Amphisomes’’, which finally fuse with the plasma membrane or lysosomes. MVs are larger than exosomes and formed from the plasma membrane through the outward budding and shedding process. EVs can affect the target cells' fate and signaling pathways in three possible ways comprising endocytosis, receptor-ligand interaction, and direct fusion with the plasma membrane

Fig. 2

Clinical application of exosomes. In clinical trials, exosomes are being used as biomarkers, cell-free therapy (exosome-therapy), drug delivery system, and cancer vaccine. Exosomes from plant cells, mesenchymal cells, T cells, and dendritic cells are used for the treatment of different diseases. In addition, exosomes from these sources are promising carriers for drug delivery systems. In the direct method, exosomes are loaded with therapeutic agents, while through indirect methods, proper cells are genetically engineered or co-cultured with therapeutic agents to produce artificial exosomes

Fig. 3

Analysis of exosome-based clinical trials

Fig. 4

Flowchart for current Good Manufacturing Practices (GMP) manufacturing of exosome therapeutic products

Fig. 5

Analysis of exosome-based biomarker clinical trials (A, B) and exosome therapy-based clinical trials for different diseases (C)