Golden Exosomes Selectively Target Brain Pathologies in Neurodegenerative and Neurodevelopmental Disorders Nisim Perets, †,§,⊥ Oshra Betzer, ‡,⊥ Ronit Shapira, ∥ Shmuel Brenstein, † Ariel Angel, † Tamar Sadan, ‡ Uri Ashery, †,∥ Rachela Popovtzer,* ,‡ and Daniel Offen* ,†,§ † Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 6997801, Israel ‡ Faculty of Engineering and the Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, Ramat Gan 5290002, Israel § Sacklar School of Medicine, Department of Human Genetics and Biochemistry, Tel Aviv University, Tel Aviv 6997801, Israel ∥ School of Neurobiology, Biochemistry and Biophysics, Life Sciences Faculty, Tel Aviv University, Tel Aviv 6997801, Israel * S Supporting Information 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. KEYWORDS: Exosomes, neuroimaging, gold nanoparticals, neuroinflammation, neurodegeneration, drug delivery D evelopment of targeted drug carriers is one of the greatest challenges for effective delivery of treatments for brain pathologies. Exosomes are emerging as potential carriers of therapeutics for such pathologies. 1,2 These lipid nanovesicles (sized 40−150 nm), secreted by numerous cell types, serve as cell-to-cell communicators 3 by transporting different proteins and nucleic acids with regulatory functions. 4 Moreover, several studies have demonstrated that mesenchymal-derived and immune cell-derived exosomes cross the blood-brain barrier following systemic or intranasal administration with no need for surface modifications. 1,5−8 We have recently shown that MSC- derived exosomes have a therapeutic effect on autistic-like behavior in the BTBR mouse model for autism. 9 As compared to cell-based therapy, which shows promise for brain pathologies, and yet holds many risks, cell-derived exosomes have the advantage of lower immunogenicity, inability to proliferate, and simple preservation and transfer. 10 The molecular features and regulatory and functional capacities of exosomes are mainly attributed to the type of cells from which they have been secreted. 11 Research shows that mesenchymal stem cell (MSC)-derived exosomes (MSC-exo) retain some of the characteristics of their parent MSCs, 4,12 such as immune system modulation, 13,14 regulation of neurite outgrowth, 15,16 promotion of angiogenesis, 17 and the ability to repair damaged tissue, such as after kidney injury. 18,19 An important question is whether MSC-exo also preserve the migration and homing abilities of parent MSCs. 20 Imaging of MSC migration in the brain has revealed specific homing to lesioned and diseased brain areas, such as in an ischemic stroke mouse model 21 and an induced rat model of Huntington’s disease, 22 using magnetic resonance imaging, and in a genetic rat model for depression, using computed tomography (CT) imaging. 23−25 It has been suggested that the therapeutic effect of MSCs on pathological regions is exerted via their secreted exosomes. 26 Received: October 16, 2018 Revised: February 10, 2019 Published: February 14, 2019 Letter pubs.acs.org/NanoLett Cite This: Nano Lett. XXXX, XXX, XXX-XXX © XXXX American Chemical Society A DOI: 10.1021/acs.nanolett.8b04148 Nano Lett. XXXX, XXX, XXX−XXX Downloaded via BAR-ILAN UNIV on May 13, 2019 at 08:07:19 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.