Glioma-Derived Exosomes and Their Application as Drug Nanoparticles

Abstract

Glioblastoma Multiforme (GBM) is the most aggressive primary tumor of the Central Nervous System (CNS) with a low survival rate. The malignancy of GBM is sustained by a bidirectional crosstalk between tumor cells and the Tumor Microenvironment (TME). This mechanism of intercellular communication is mediated, at least in part, by the release of exosomes. Glioma-Derived Exosomes (GDEs) work, indeed, as potent signaling particles promoting the progression of brain tumors by inducing tumor proliferation, invasion, migration, angiogenesis and resistance to chemotherapy or radiation. Given their nanoscale size, exosomes can cross the blood-brain barrier (BBB), thus becoming not only a promising biomarker to predict diagnosis and prognosis but also a therapeutic target to treat GBM. In this review, we describe the structural and functional characteristics of exosomes and their involvement in GBM development, diagnosis, prognosis and treatment. In addition, we discuss how exosomes can be modified to be used as a therapeutic target/drug delivery system for clinical applications.

Keywords: exosomes; glioblastoma multiforme; glioma-derived exosomes; tumor microenvironment.

Figure 1

Overview of the exosome’s biogenesis. Cargoes are internalized and sorted into Early Endosome (EE), which then mature into MVBs. Cargoes are also delivered by the trans-Golgi network and possibly by the cytosol. Multivesicular bodies containing cargoes of exosomes are transported to the Plasma Membrane (PM), where they fuse with the cell surface, and ILVs are then secreted as exosomes. Created with BioRender.

Figure 2

Schematic representation of glioma tumor microenvironment. Created with BioRender.

Figure 3

Exosomes are composed of different proteins: transmembrane proteins such as tetraspanins, antigen-presenting molecules, glycoproteins and adhesion molecules; proteins in exosome cargo such as cytoskeletal proteins, Endosomal Sorting Complexes required for Transport (ESCRT) components, membrane transport, fusion proteins and cytokines; nucleic acids; multiple lipids such as cholesterol or ceramides. Created with BioRender.

Figure 4

Schematic representation of the mechanisms by which GDEs can enhance GBM aggressiveness (A) and how GDEs can be used for tumor suppressive purposes (B). Examples of tumor-enhancing mechanisms of GDE are (1) delivery of an exosomal cargo with oncogenetic miRNAs, (2) induction of drug resistance, (3) tumor-supporting function of GDE derived from the TME enhancing glioma cells aggressiveness in terms of tumor growth and infiltrative nature, (4) induction of an immunosuppressive TME and (5) promotion of GBM angiogenesis. Examples of how to exploit exosomes as anti-tumor factors are (6) defining a possible oncosuppressive GDE cargo, (7) using GDE as a drug-delivery system, taking advantage of both their ability to cross the blood–brain barrier and to be highly internalized by glioma cells, (8) silencing oncogenetic GDE cargo or engineering exosomes with peptides, (9) using GDEs in GBM immunotherapy. Created with BioRender.

Figure 5

Overview of exosome classification. According to EV origin, exosomes can be divided into natural, modified and synthetic. Created with BioRender.

Figure 6

Schematic representation of the different methods for isolating natural exosomes. Created with BioRender.

Figure 7

Schematic representation of the two possible exosome modifications: surface or internal modifications. Internal modifications can be distinguished, depending on the timing, in pre-isolation and post-isolation modification methods. Created with BioRender.

Figure 8

Principle of pre-isolation exosome modification methods: co-incubation and gene editing performed before isolating exosomes from parental cells. Created with BioRender.

Figure 9

Principle of exosome modification methods post-isolation: passive and active incorporation methods performed after isolating exosomes from parental cells (a). Schematic representation of the two possible modifications (b). Created with BioRender.

Figure 10

Principle of surface modification methods: gene engineering of parental cells and direct modification of isolated exosomes. Created with BioRender.

Figure 11

Schematic representation of the two possible modifications: cell-based methodology and lipid membrane bilayer formation methodology incorporation. Created with BioRender.