Virtually, all cells in the organism will secrete extracellular vesicles (EVs), a heterogeneous population of lipid bilayer membrane enclosed vesicles that transport and deliver payloads of proteins recipient cells, thus playing critical roles in cell communications. Exosomes, nanosized EVs of endosomal origin, regulate many pathophysiological processes. The exosomes as natural carriers of functional small RNA and proteins have raised great interest in the drug delivery research field, as it may be possible to harness these vesicles for therapeutic delivery of synthetic drugs. On the outer surface, targeted exosomes can be obtained by displaying targeting molecules, such as peptides or antibody fragments. In target cells, exosomes could serve drug targets and provide a new sight for therapy.
Early studies have investigated exosomes from various cells. For example, mature dendritic cells (DCs) secrete exosomes presenting antigens to the immune system and DC-derived exosomes facilitated immune cell-dependent tumor rejection. The T-cell receptor is located on the surface of microvesicles that budding at the immunological synapse center. B cells bearing cognate major histocompatibility complex (MHC) proteins receive T-cell receptors from T cells. Activated T cells release miRNA loaded exosomes that regulated immunity by targeting APCs. Donor DC-derived exosomes promoted alloimmune responses. Besides, a recent study illustrated that exosomal miR-146a and miR-155 passed between immune cells in vivo, and endotoxin-induced inflammation was inhibited by exosomal miR-146a in mice. Placenta derive EVs can suppress maternal immune rejection through inhibiting T-cell signaling and by promoting apoptosis of activated lymphocytes through the display of Fas ligand and tumor necrosis factor (TNF)-related apoptosis-inducing ligand.
Exosomes are prominently involved in shuttling reciprocal signals between myelinating glia and neurons, thus promoting neuronal survival, and immune responses mediated by microglia, and synapse assembly, and plasticity while also playing important roles in the spread of neurodegenerative disorders and brain cancer. Circulating exosomes from patients with Parkinson disease protected neurons against stress. Besides, beta-amyloid peptide released from the cells in association with exosomes accumulated in the brain of patients with Alzheimer disease. On the other hand, EVs participate in the packaging and spread of misfolded proteins associated with neurodegenerative diseases. Scientists also find that the neutral sphingomyelinase pathway was shown to regulate the packaging of the prion protein into exosomes.
Tumor-derived exosomes trigger potent T-cell mediated anti-tumor immune responses. Tumor-derived exosomes deliver proangiogenic peptides and miRNAs to microvascular endothelial cells to promote tumor angiogenesis. Glioma cells were shown to deliver EGFR via EVs to surrounding glioma cells, in which EGFR activated transforming signaling pathways and regulated the expression of target genes including vascular endothelial growth factor (VEGF), anti-apoptotic Bcl-x, and cyclin-dependent kinase inhibitor p27. These findings illustrate EVs mediated bi-directional crosstalk between tumor and non-tumor cells.
As mentioned above, exosomes can be harnessed for both diagnostic and therapeutic purposes, which could help us develop drug targets in the family of exosomes. Naturally, engineered exosome mimetics are assembled using controllable procedures that may be more acceptable pharmaceutically, which is helpful for the cure of illness. Therefore, exosomes could provide new sight for drug discovery.