Leveraging Exosomes as the Next-Generation Bio-Shuttles: The Next Biggest Approach against Th17 Cell Catastrophe

Abstract

In recent years, the launch of clinical-grade exosomes is rising expeditiously, as they represent a new powerful approach for the delivery of advanced therapies and for diagnostic purposes for various diseases. Exosomes are membrane-bound extracellular vesicles that can act as biological messengers between cells, in the context of health and disease. In comparison to several lab-based drug carriers, exosome exhibits high stability, accommodates diverse cargo loads, elicits low immunogenicity and toxicity, and therefore manifests tremendous perspectives in the development of therapeutics. The efforts made to spur exosomes in drugging the untreatable targets are encouraging. Currently, T helper (Th) 17 cells are considered the most prominent factor in the establishment of autoimmunity and several genetic disorders. Current reports have indicated the importance of targeting the development of Th17 cells and the secretion of its paracrine molecule, interleukin (IL)-17. However, the present-day targeted approaches exhibit drawbacks, such as high cost of production, rapid transformation, poor bioavailability, and importantly, causing opportunistic infections that ultimately hamper their clinical applications. To overcome this hurdle, the potential use of exosomes as vectors seem to be a promising approach for Th17 cell-targeted therapies. With this standpoint, this review discusses this new concept by providing a snapshot of exosome biogenesis, summarizes the current clinical trials of exosomes in several diseases, analyzes the prospect of exosomes as an established drug carrier and delineates the present challenges, with an emphasis on their practical applications in targeting Th17 cells in diseases. We further decode the possible future scope of exosome bioengineering for targeted drug delivery against Th17 cells and its catastrophe.

Keywords: Th17 cell; drug delivery vector; exosome engineering; packaging therapeutics.

Figure 1

Detailed schematic overview of exosome biogenesis and inhibitors that block the release of exosomes within the endosomal system. The formation of exosomes involves the inward budding and fusion of the limiting membrane of endocytic vesicles that engender intraluminal vesicles (ILVs). The maturation process of ILVs can be through endosomal complexes required for transport (ESCRT)-dependent and -independent mechanisms that process cargo sorting and formation of multivesicular bodies (MVBs). Components of MVBs can then be integrated into the membranes for release into the extracellular space or may be guided for lysosomal degradation. Exosomal contents released into the extracellular space can then be internalized by the target cell via membrane fusion, ligand-receptor conformation or endocytosis mechanism. This illustration further comprehends various chemical inhibitors, including SMase inhibitors, exosome release inhibitors and Rab inhibitors (depicted in black rectangular boxes) that prevent exosome biogenesis and secretion within the endosomal compartment. The sequential steps on exosome biogenesis follows: 1. Exosome formation; 2. Cargo sorting; 3. MVBs formation; 4. Exosome release; 5. Exosome-target cell interaction; 6. Cargo release into cytosol of target cells; 7. MVBs endosome recycling; and 8. Lysosome degradation of exosomes. Abbreviations: Rab; Ras associated binding protein, SNARE; SNAP receptor.

Figure 2

Pictorial representation of exosomal targets that participate during the T helper (Th)17 cell developmental stages and in promoting its effector function. Early activation of antigen-presenting cells (APCs) mounts an immune response that releases Th17 cell polarizing cytokines, such as IL-6, IL-23, IL-12, etc. These cytokines interact with the receptor on CD4⁺ T cells and induce its polarization to the Th17 cell phenotype via activation of intermediate kinases and transcription factors. Differentiated Th17 cells then migrate via the bloodstream to inflammatory sites and execute effector function. Furthermore, the diagram highlights multi-targets, including cytokines or its receptor, transcriptional factors or RNA-binding proteins that can be modulated via exosomal anti-Th17 therapies. Abbreviations: PAMPs; pathogen-associated molecular pattern molecules, STAT-3; signal transducer and activator of transcription 3, ZEB1; zinc finger E-box binding homeobox 1, AhR; aryl hydrocarbon receptor, YY1; yin yang 1, IMP2; IGF2 mRNA binding protein 2, TGF-β; transforming growth factor β, TCR; T cell receptor, CCL2; chemokine (C-C motif) ligand 2, REV-ERBα; nuclear receptor subfamily 1group D, ROR-γT; retinoic acid-related orphan receptor gamma t, HuR; human antigen R.

Figure 3

Diagrammatic illustration of exosome engineering for loading molecules into the lumen or sorting them on their surface for specific targeting of Th17 cells. Exosomes are engineered to express CD30 or CD4 aptamer, peptide targeting α_vβ₃ and Vi polysaccharide (targets prohibitins) on their surface using different sorting modules that result in a sustained response against Th17 cells. Furthermore, the packaging substances including drugs, nucleic acid molecules, etc., can be loaded onto the engineered exosomes for targeting Th17 cells to inhibit its pathogenic mechanism in diseases. Abbreviations: PROCR; protein C receptor, MHC; major histocompatibility complex.