Exosomes as therapeutic and drug delivery vehicle for neurodegenerative diseases

Abstract

Neurodegenerative disorders are complex, progressive, and life-threatening. They cause mortality and disability for millions of people worldwide. Appropriate treatment for neurodegenerative diseases (NDs) is still clinically lacking due to the presence of the blood-brain barrier (BBB). Developing an effective transport system that can cross the BBB and enhance the therapeutic effect of neuroprotective agents has been a major challenge for NDs. Exosomes are endogenous nano-sized vesicles that naturally carry biomolecular cargoes. Many studies have indicated that exosome content, particularly microRNAs (miRNAs), possess biological activities by targeting several signaling pathways involved in apoptosis, inflammation, autophagy, and oxidative stress. Exosome content can influence cellular function in healthy or pathological ways. Furthermore, since exosomes reflect the features of the parental cells, their cargoes offer opportunities for early diagnosis and therapeutic intervention of diseases. Exosomes have unique characteristics that make them ideal for delivering drugs directly to the brain. These characteristics include the ability to pass through the BBB, biocompatibility, stability, and innate targeting properties. This review emphasizes the role of exosomes in alleviating NDs and discusses the associated signaling pathways and molecular mechanisms. Furthermore, the unique biological features of exosomes, making them a promising natural transporter for delivering various medications to the brain to combat several NDs, are also discussed.

Keywords: Exosome; Neurodegenerative diseases; Targeted drug delivery.

Fig. 1

Schematic presentation of exosome structure and composition. CD, Cluster of differentiation; HSP, Heat shock proteins; ICAM, Intercellular adhesion molecule; TSG101, Tumor susceptibility gene 101; GAPDH, Glyceraldehyde-3-phosphate dehydrogenase; TGF–β, Transforming growth factor β; TNF-α, Tumor necrosis factor α; pgk1, Phosphoglycerate kinase; TRAIL, TNF-related apoptosis-inducing ligand; MHC, Major histocompatibility complex; Lamp, Lysosomal associated membrane protein

Fig. 2

Exosomes and exosomes-derived miRNAs can interface several signaling pathways involved in autophagy. Bcl-2, B-cell lymphoma 2; BNIP, BCL2/adenovirus E1B 19 kd-interacting protein; mTOR, Mammalian target of rapamycin; EGFR, Epidermal growth factor receptor; STAT, Signal transducer and activator of transcription; ULK, Unc-51 like autophagy activating kinase; VPS34, Vacuolar protein-sorting 34; ATG, Autophagy-related protein; LC3, Light chain 3

Fig. 3

Main signaling pathways involved in apoptosis influenced by exosomes and exosomes-derived miRNAs. PI3K/AKT, Phosphatidylinositol-3 kinase/AKT; PTEN, Phosphatase and tensin homolog; BAX, Bcl-2-associated X protein; Apaf-1, Apoptotic protease activating factor-1; FASL, Fas ligand; miR, microRNA

Fig. 4

Numerous therapeutic targets affected by exosomes and exosomes-derived miRNAs toward modulating inflammation and oxidative stress. AMPK, (AMP)-activated protein kinase; PI3K/AKT, Phosphatidylinositol-3 kinase/AKT; Nrf2/ARE, Nuclear factor E2-related factor 2/ antioxidant response element; SIRT, Sirtuin; OPA1, Optic atrophy 1; ANT2, Adenine nucleotide translocator 2; SOD, Superoxide dismutase; HO-1, Hemoxygenase-1; NQO-1, NAD(P)H quinone dehydrogenase1; GST, Glutathione S-transferase; IL, Lnterleukin; TNF-α, Tumor Necrosis Factor-α; SOCS, Suppressor of cytokine signaling; ERK, Extracellular-signal-regulated kinase; JNK, c-Jun N terminal kinase; NF-κB, Nuclear factor-κB; IRAK, Interleukin-1 receptor-associated kinase; TRAF, Tumor necrosis factor receptor-associated factor; TLR, Toll-like receptor; MyD88, Myeloid differentiation factor 88; TAK, Transforming Growth Factor (TGF)-β-activated Kinase; NADPH, Nicotinamide adenine dinucleotide phosphate; IKK, Ikappa kinase

Fig. 5

Structural difference between the cerebral and non-cerebral capillaries. Reprinted from Ref [73] with permission from John Wiley and Sons

Fig. 6

Therapeutic potential of exosomes in different types of NDs. Reprinted from Ref [8] with permission from Elsevier