Golden Exosomes Selectively Target Brain Pathologies in Neurodegenerative and Neurodevelopmental Disorders

Abstract

Exosomes, nanovesicles that are secreted by different cell types, enable intercellular communication at local or distant sites. Alhough they have been found to cross the blood brain barrier, their migration and homing abilities within the brain remain unstudied. We have recently developed a method for longitudinal and quantitative in vivo neuroimaging of exosomes based on the superior visualization abilities of classical X-ray computed tomography (CT), combined with gold nanoparticles as labeling agents.Here, we used this technique to track the migration and homing patterns of intranasally administrated exosomes derived from bone marrow mesenchymal stem cells (MSC-exo) in different brain pathologies, including stroke, autism, Parkinson's disease, and Alzheimer's disease. We found that MSC-exo specifically targeted and accumulated in pathologically relevant murine models brains regions up to 96 h post administration, while in healthy controls they showed a diffuse migration pattern and clearance by 24 h. The neuro-inflammatory signal in pathological brains was highly correlated with MSC-exo accumulation, suggesting that the homing mechanism is inflammatory-driven. In addition, MSC-exo were selectively uptaken by neuronal cells, but not glial cells, in the pathological regions. Taken together, these findings can significantly promote the application of exosomes for therapy and targeted drug delivery in various brain pathologies.

Prospects and challenges of extracellular vesicle-based drug delivery system: considering cell source

“…From then on, MEVs have been increasingly considered as substitutes for MSCs in drug delivery. Efforts have been made to improve the efficacy of MEV-based drug delivery for clinical use (Cheng et al, 2018b;Lang et al, 2018;Sharif et al, 2018;Jo et al, 2019;Li et al, 2019a;Perets et al, 2019;Riazifar et al, 2019). For example, a good manufacturing practice (GMP) standard for large-scale clinical MEVs production based on bioreactor has been established (Mendt et al, 2018).…”

“…They showed that these gold-iron oxide rich EVs achieved excellent T2 contrast MRI and resulted in efficient photothermal effect in 4T1 cells. Recently, Perets et al (2019) developed a method for longitudinal and quantitative in vivo neuroimaging of exosomes based on the superior visualization abilities of classical X-ray computed tomography (CT), combined with gold nanoparticles as labeling agents. Upon administered intranasally, gold nanoparticle-labeled exosomes could be efficiently tracked by CT (Perets et al, 2019).…”

“…Recently, Perets et al (2019) developed a method for longitudinal and quantitative in vivo neuroimaging of exosomes based on the superior visualization abilities of classical X-ray computed tomography (CT), combined with gold nanoparticles as labeling agents. Upon administered intranasally, gold nanoparticle-labeled exosomes could be efficiently tracked by CT (Perets et al, 2019). EVs loaded with metal nanoparticles provide a potential alternative diagnostic methodology for various pathological conditions.…”

Advances in imaging strategies for in vivo tracking of exosomes

“…Recent papers used CT for tracking intranasally (IN) administered gold-labeled exosomes within the brain (Betzer, Perets, et al, 2017;Betzer, Perets, Barnoy, Offen, & Popovtzer, 2018;Perets et al, 2019). A protocol for direct labeling of exosomes with gold nanoparticles (GNP) was developed.…”

MRI tracking reveals selective accumulation of stem cell-derived magneto-extracellular vesicles in sites of injury

“…Before this, EV imaging and tracking methods can serve as a guide to direct the development, optimization, and implementation of EV-based therapeutics. To date, considerable effort has been devoted to develop EV tracking methods using fluorescence imaging (14,15), bioluminescence imaging (16), single-photon emission computed tomography (SPECT) (17), positron emission tomography (PET) (18), computed tomography (CT) (19,20), magnetic resonance imaging (MRI) (21,22), and magnetic particle imaging (23). Among them, MRI is an appealing imaging modality that is used widely in the clinic and has excellent soft-tissue contrast without using ionizing radiation.…”