Exosomes as a Nanodelivery System: a Key to the Future of Neuromedicine?

Abstract

Since the beginning of the last decade, exosomes have been of increased interest in the science community. Exosomes represent a new kind of long distance transfer of biological molecules among cells. This review provides a comprehensive overview about the construction of exosomes, their targeting and their fusion mechanisms to the recipient cells. Complementarily, the current state of research regarding the cargo of exosomes is discussed. A particular focus was placed on the role of exosomes in the central nervous system. An increasing number of physiological processes in the brain could be associated with exosomes. In this context, it is becoming more apparent that exosomes are involved in several neurological and specifically neurodegenerative diseases. The treatment of these kinds of diseases is often difficult not least because of the blood-brain barrier. Exosomes are very stable, can pass the blood-brain barrier and, therefore, reveal bright perspectives towards diagnosis and therapeutic treatments. A prerequisite for clinical applications is a standardised approach. Features necessary for a standardised diagnosis using exosomes are discussed. In therapeutic terms, exosomes represent a promising drug delivery system able to pass the blood-brain barrier. One option to overcome the disadvantages potentially associated with the use of endogenous exosomes is the design of artificial exosomes. The artificial exosomes with a clearly defined therapeutic active cargo and surface marker ensuring the specific targeting to the recipient cells is proposed as a promising approach.

Keywords: Artificial exosome; Diagnosis; Extracellular vesicles; MicroRNA; Multiple sclerosis; Neurodegenerative disease.

Fig. 1

Formation and release of exosomes. a Exosome formation initiates by inward budding of plasma membrane to form MVBs. By formation of MVBs, receptors on the surface of plasma membrane locate inside the MVBs (1–3). Inward budding of MVBs results in the formation of internal vesicles inside the MVBs (4–5). By this stage, internal vesicles carry components from inside the cell such as cytosolic proteins or RNAs. Designated targeting molecules such as receptors are located on the outer surface of these vesicles similar to their location on the plasma membrane of the cell. b There are two possible destinations for the MVBs, which contain the internal vesicles. Either they are digested by lysosomes (6) or the MVB membrane fuses with the plasma membrane to release the internal vesicles now called exosomes (7). After reaching to their target cell, exosomes deliver their cargo either by adhesion via members of integrin family (8), via receptor ligand interaction (9) and/or via internalisation by endocytosis (10). c Exosomes deliver their cargo to the target cell either by fusion (left part) or hemifusion (right part). Fusion: the membrane of exosome and the target cell merge and result in an interconnected structure. Hemifusion: after releasing of cargo, the exosome membrane disconnected again from the plasma membrane of the target cell. MVB multivesicular body

Fig. 2

Active role of exosomes in the central nervous system. a Exosomes play a crucial role in synaptic plasticity. Syt4 is a membrane-trafficking protein and is essential for retrograde signalling. It was observed that exosome containing Syt4 (demonstrated by brown circles, indicated with dark arrows heads) are released from presynaptic terminal and thereby the entire pool of Syt4 in postsynaptic terminal is provided by exosomes from the presynaptic terminal. The yellow arrow presents the release of neurotransmitters (yellow triple-circle shapes) from presynaptic terminal and binding of them to neurotransmitter receptors (orange two-circle shapes). Release of neurotransmitters allows entry of Ca²⁺ to the presynaptic terminal and activates fusion of exosome-containing MVBs to the plasma membrane. b In the CNS, different cell types such as neurons, oligodendrocytes and microglia release exosomes (exosomes of each cell type are performed by small circles coloured in parental cell colour). Released exosomes reach different cell type in distance and deliver their cargo to other cells. Therefore, cells in the CNS can communicate with each other and help to regulate their function. c Exosomes derived from resident cells in the CNS can pass through the BBB. Mast cell-derived exosomes (dark blue circles) can pass through the BBB and are able to activate B and T cells or induces DCs to become efficient antigen-presenting cells. B cell-derived exosomes, in turn, can stimulate T cells or transfer MHC class II proteins to the surface of follicular DCs, which do not express these molecules