Glutathione targeted tragacanthic acid-chitosan as a non-viral vector for brain delivery of miRNA-219a-5P: An in vitro/in vivo study

Multiple sclerosis (MS) is a progressive chronic demyelinating and neurodegenerative disease. The symptoms could only be diminished through stimulated remyelination. Although administration of microRNA-219a-5P (miR-219) seems to recover the damages, it is hampered by the challenging delivery of genes to the central nervous system across the blood-brain barrier. To enhance the CNS delivery of miR-219, a novel non-viral targeted vector was appraised by conjugating chitosan (Ch) to tragacanthic acid (TA) and glutathione (Glu). The nanoparticles were characterized and injected into the cuprizone model of MS mice to investigate the in vivo features of the resulting polyplex. Transmission electron microscopy, luxol fast blue staining, and proteolipid protein 1 (Plp1) overexpression confirmed more compact myelin sheaths following the administration of the targeted miR-219 nanoparticles and positron emission tomography (PET) scan also demonstrated the reduced inflammation and higher cell regeneration in the brain. Fluorescence microscopy and in vivo imaging were employed to identify miR-219 accumulation patterns in mice. The polyplex led to miR-219 overexpression, crystallin alpha B upregulation, and apolipoprotein E downregulation. It was concluded that glutathione targeted Ch/TA nanoparticles could be exploited as a feasible non-viral vector for miR-219 specific targeting to the brain, miR-219 overexpression and inflammation abatement in MS.