Exosomes as therapeutic drug carriers and delivery vehicles across biological membranes: current perspectives and future challenges

Abstract

Exosomes are small intracellular membrane-based vesicles with different compositions that are involved in several biological and pathological processes. The exploitation of exosomes as drug delivery vehicles offers important advantages compared to other nanoparticulate drug delivery systems such as liposomes and polymeric nanoparticles; exosomes are non-immunogenic in nature due to similar composition as body׳s own cells. In this article, the origin and structure of exosomes as well as their biological functions are outlined. We will then focus on specific applications of exosomes as drug delivery systems in pharmaceutical drug development. An overview of the advantages and challenges faced when using exosomes as a pharmaceutical drug delivery vehicles will also be discussed.

Keywords: ALIX, ALG-2 interacting protein X; ATPase, adenosine triphosphatase; BBB, blood–brain barrier; CCK-8, cell counting kit-8; CD, cluster of differentiation; DIL, 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate; DNA, deoxyribonucleic acid; Drug delivery systems; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; ESCRT, endosomal sorting complexes required for transport; EV, extracellular vesicle; EpCAM, epithelial cell adhesion molecule; Exosomes; Extracellular vesicles; HEK293, human embryonic kidney cell line 293; HIV, human immunodeficiency virus; HMGA2, high-mobility group AT-hook protein; HeLa, Henrietta Lacks cells; Hsp, heat shock proteins; IL-6, interleukin-6; ILVs, intraluminal vesicles; LPS, lipopolysaccharides; MAPK-1, mitogen-activated protein kinase 1; MHC, major histocompatibility complex; MPS, mononuclear phagocyte system; MVB, multi-vesicular body biogenesis; Nanocarrier; PBMC, peripheral blood mononuclear cells; PD, Parkinson’s disease; PEG, polyethylene glycol; RNA, ribonucleic acid; ROS, reactive oxygen species; RPE1, retinal pigment epithelial cells 1; TNF-α, tumor necrosis factor α; TSG101, tumor susceptibility gene 101; VPS4, vacuolar protein sorting-associated protein 4; kRAS, Kirsten rat sarcoma; mRNA, messenger RNA; miRNA, micro RNA; siRNA, small interference RNA.

Graphical abstract

Figure 1

Types of microvesicles. Exosome with sizes ranging 40–100 nm (left), microvesicles with sizes ranging 50–1000 nm (middle), apoptotic body size ranging 50–5000 nm (right).

Figure 2

Formation of exosome and microvesicle. Exosome is derived from endosome formed from plasma membrane. As early endosome becomes late endosomes, inward budding occurs and forms multivesicular bodies (MVB) containing numerous intraluminal vesicles (ILV). MVB can either get degraded by lysosomes or fuse with the membrane to release ILV called exosomes. Micorvesicles, on the other hand, originate from the budding of the plasma membrane.

Figure 3

Composition of exosomes. Exosomes are composed of various types of proteins, such as major histocompatibility complex (MHC)-II, integrin, cluster of differentiation (CD), tetraspanins, heat shock protein (Hsp), Ras-related protein (Rab), etc. Exosomes also contain various types of lipids, such as sphingomyelin and cholesterol. Lastly, exosomes are found to contain nucleic acid, including miRNA, mRNA and non-coding RNAs.

Figure 4

Formation of exosomal curcumin. Curcumin was incorporated into murine tumor cell line (EL-4), derived exosomes and isolated using sucrose gradient centrifugation.

Figure 5

Ability of exosome and its drug contents to cross the blood–brain barrier.