Journal
BIOMATERIALS
Volume 142, Issue -, Pages 1-12Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2017.07.011
Keywords
BBB; Endocytosis; Inflammation; Macrophage exosomes; Pharmacokinetics; Protein delivery
Funding
- National Institutes of Health [1R21 NS088152, RO1 NS36229]
- Rettsyndrome.org HeART Award [3112]
- Carolina Partnership
- UNC Eshelman School of Pharmacy
- University Cancer Research Fund
- Cancer Center Core Support Grant [P30 CA016086]
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Recent work has stimulated interest in the use of exosomes as nanocarriers for delivery of small drugs, RNAs, and proteins to the central nervous system (CNS). To overcome the blood-brain barrier (BBB), exosomes were modified with brain homing peptides that target brain endothelium but likely to increase immune response. Here for the first time we demonstrate that there is no need for such modification to penetrate the BBB in mammals. The naive macrophage (M phi) exosomes can utilize, 1) on the one hand, the integrin lymphocyte function-associated antigen 1 (LFA-1) and intercellular adhesion molecule 1 (ICAM-1), and, 2) on the other hand, the carbohydrate-binding C-type lectin receptors, to interact with brain microvessel endothelial cells comprising the BBB. Notably, upregulation of ICAM-1, a common process in inflammation, promotes M phi exosomes uptake in the BBB cells. We further demonstrate in vivo that naive M phi exosomes, after intravenous (IV) administration, cross the BBB and deliver a cargo protein, the brain derived neurotrophic factor (BDNF), to the brain. This delivery is enhanced in the presence of brain inflammation, a condition often present in CNS diseases. Taken together, the findings are of interest to basic science and possible use of M phi-derived exosomes as nanocarriers for brain delivery of therapeutic proteins to treat CNS diseases. (C) 2017 Elsevier Ltd. All rights reserved.
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