Intranasal Delivery of Mesenchymal Stem Cells-Derived Extracellular Vesicles for the Treatment of Neurological Diseases

Abstract

Neurological disorders are diseases of the central nervous system (CNS), characterized by a progressive degeneration of cells and deficiencies in neural functions. Mesenchymal stem cells (MSCs) are a promising therapy for diseases and disorders of the CNS. Increasing evidence suggests that their beneficial abilities can be attributed to their paracrine secretion of extracellular vesicles (EVs). Administration of EVs that contain a mixture of proteins, lipids, and nucleic acids, resembling the secretome of MSCs, has been shown to mimic most of the effects of the parental cells. Moreover, the small size and safety profile of EVs provide a number of advantages over cell transplantation. Intranasal (IN) administration of EVs has been established as an effective and reliable way to bypass the blood-brain barrier and deliver drugs to the CNS. In addition to pharmacological drugs, EVs can be loaded with a diverse range of cargo designed to modulate gene expression and protein functions in recipient cells, and lead to immunomodulation, neurogenesis, neuroprotection, and degradation of protein aggregates. In this review, we will explore the proposed physiological pathways by which EVs migrate through the nasal route to the CNS where they can actively target a region of injury or inflammation and exert their therapeutic effects. We will summarize the functional outcomes observed in animal models of neurological diseases following IN treatment with MSC-derived EVs. We will also examine key mechanisms that have been suggested to mediate the beneficial effects of EV-based therapy.

Gene-Directed Enzyme/Prodrug Therapy of Rat Brain Tumor Mediated by Human Mesenchymal Stem Cell Suicide Gene Extracellular Vesicles In Vitro and In Vivo

“…A noninvasive intranasal application route for suicide gene EVs was found to be quite effective in confirming our previous findings showing migration of dental pulp-derived MSCs labeled with iron sucrose to intracerebral glioblastoma in rats [28]. Intranasal delivery of MSC-derived extracellular vesicles seems to be a very promising way of administrating therapeutics in regenerative medicine, which has been recently comprehensively reviewed [29].…”

Regenerative Neurology and Regenerative Cardiology: Shared Hurdles and Achievements

“…However, pharmacokinetic studies in vivo have shown that EVs can be very quickly removed from the bloodstream, with a majority of them being = entrapped in the liver and the lungs [ 110 ]. Accordingly, several groups investigated alternative delivery via minimally invasive intranasal route [ 111 , 112 ]. The EVs secreted by mouse macrophages were permeabilized, loaded with antioxidant enzyme catalase and applied intranasally to 6-hydroxydopamine (6-OHDA) mice [ 113 ].…”

Mesenchymal Stem Cell-Derived Extracellular Vesicles for the Treatment of Bronchopulmonary Dysplasia

“…Most important of all, the appropriate children, treatment time, appropriate pathway, and effective dose of MSC-EVs need to be determined ( 66 – 68 ). The main delivery methods of extracellular vesicles are intratracheal administration, nasal inhalation, Intraperitoneal injection, and intravenous administration ( 37 , 38 , 69 , 70 ). As for which pathway of administration is better and how much are the dosage, further research is still needed.…”