High-efficiency brain-targeted intranasal delivery of BDNF mediated by engineered exosomes to promote remyelination

Abstract

The regeneration of myelin sheath is the ultimate therapeutic goal of demyelination disease, including multiple sclerosis (MS). However, current drugs for MS mainly targeting the immune system, which can only...

Smart Nanoscale Extracellular Vesicles in the Brain: Unveiling their Biology, Diagnostic Potential, and Therapeutic Applications

“…Interestingly, the effect was observed at low doses of Bryo-2 (1 × 10 8 particles) when encapsulated in the EVs compared to the systemic delivery of Bryo-1 alone . The regeneration of myelin sheaths and improved motor abilities were also achieved when BDNF-loaded EVs were delivered in the mice models of MS . Here, the authors mainly highlight the mode of EV delivery (intranasal) to increase the efficiency of the therapy, suggesting that the delivery modes also impact EV functioning and availability to the targeted site.…”

“…Interestingly, the effect was observed at low doses of Bryo-2 (1 × 10 8 particles) when encapsulated in the EVs compared to the systemic delivery of Bryo-1 alone. 221 The regeneration of myelin sheaths and improved motor abilities were also achieved when BDNFloaded EVs were delivered in the mice models of MS. 222 Here, the authors mainly highlight the mode of EV delivery (intranasal) to increase the efficiency of the therapy, suggesting that the delivery modes also impact EV functioning and availability to the targeted site. Apart from the neural origin, EVs from other cell types are also shown to mediate neuroprotection in MS. For instance, Jia et al overexpressed the Treg gene FOXP3 in the dendritic cells and observed that the exosomes released from them, when cocultured with CD4+ cells, could suppress their proliferation and immune phenotype.…”

The role of exosomes in central nervous system tissue regeneration and repair

“…However, BDNF has a poor ability to cross the BBB. Recently, our study successfully loaded the mRNA and protein of BDNF onto exosomes, which can promote the differentiation of OPCs into mature oligodendrocytes in vitro and had a significant therapeutic effect on remyelination and motor coordination ability improvement in demyelination model mice via intranasal administration [42]. Another study also proved that BDNF could be loaded onto exosomes derived from BDNF-overexpressing HEK293 cells, regulating the internal cellular environment and inhibiting apoptosis [43].…”

Biomaterials-Enhanced Intranasal Delivery of Drugs as a Direct Route for Brain Targeting

“…SLNs and NLPs have shown higher drug loading, better drug stability and prolonged release profile compared to liposomes [ 74 , 75 ]. Finally, exosomes, naturally derived nanocarriers secreted by cells, have recently attracted interest as drug delivery systems for the treatment of brain disorders through IN administration thanks to their low immunogenicity, good biocompatibility, possibility of functionalization for targeted action and broad spectrum of endogenous and exogenous bioactive cargo molecules, including protein, nucleic acids, growth factors and therapeutic agents [ 65 , 67 , 76 ]. Interestingly, the nanocarrier surface has been frequently functionalized with: Muco-adhesive polymers such as chitosan or polymer containing thiol groups (thiomers); Molecules for adsorption endocytosis by the epithelial layer (e.g., lectins, cell-penetrating peptides, such as penetratin, Tat peptide, etc.…”

“…Yang et al prepared liposomes loaded with rivastigmine and surface functionalized with a cell-penetrating peptide [ 64 ]. Zhai et al modified the surface of exosomes with rabies virus glycoprotein (RVG) peptide able to specifically bind to neuronal acetylcholine receptor for the delivery of brain-derived neurotrophic factor for multiple sclerosis applications [ 67 ]. Finally, Peng et al proposed a novel nanocarrier system, characterized by a polymer micellar core composed of PPS−PEG, encapsulated in an exosome outer shell modified with penetratin and RVG peptides for the delivery of curcumin for Parkinson’s disease treatment [ 66 ].…”