4.8 Article

Targeting central nervous system extracellular vesicles enhanced triiodothyronine remyelination effect on experimental autoimmune encephalomyelitis

Journal

BIOACTIVE MATERIALS
Volume 9, Issue -, Pages 373-384

Publisher

KEAI PUBLISHING LTD
DOI: 10.1016/j.bioactmat.2021.07.017

Keywords

Extracellular vesicles; Neuroinflammation; Multiple sclerosis; Drug delivery; Experimental autoimmune encephalomyelitis; T3

Funding

  1. Chinese National Natural Science Foundation [31970771, 82071396, 81771345]
  2. Shaanxi Provincial Key RD Foundation [2021ZDLSF03-09]
  3. Science and Technology Projects of Ningxia Autonomous Region Key RD Programs [2018BFG02017]
  4. Natural Science Foundation of Ningxia Province, China [2020AAC03397]
  5. Fundamental Research Funds for the Central Universities [GK202007022, GK202105002, TD2020039Y, 2020CSLZ009, 2021CSZL008]

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The lack of targeted and high-efficiency drug delivery to the central nervous system (CNS) nidus is a major problem in treating demyelinating diseases. This study developed a novel therapeutic system using engineered extracellular vesicles (EVs) from neural stem cells (NSCs) with high expressed ligand PDGF-A (EVPs) for local delivery targeting oligodendrocyte lineage. Experimental results demonstrated that systemic injection of EVPs + T3, as compared to EVPs or T3 alone, significantly alleviated disease progression, enhanced oligodendrocyte survival, inhibited myelin damage, and promoted myelin regeneration in mice with experimental autoimmune encephalomyelitis.
The lack of targeted and high-efficiency drug delivery to the central nervous system (CNS) nidus is the main problem in the treatment of demyelinating disease. Extracellular vesicles (EVs) possess great promise as a drug delivery vector given their advanced features. However, clinical applications are limited because of their inadequate targeting ability and the dilution effects after systemic administration. Neural stem cells (NSCs) supply a plentiful source of EVs on account of their extraordinary capacity for self-renewal. Here, we have developed a novel therapeutic system using EVs from modified NSCs with high expressed ligand PDGF-A (EVPs) and achieve local delivery. It has been demonstrated that EVPs greatly enhance the target capability on oligodendrocyte lineage. Moreover, EVPs are used for embedding triiodothymnine (T3), a thyroid hormone that is critical for oligodendrocyte development but has serious side effects when systemically administered. Our results demonstrated that systemic injection of EVPs + T3, versus EVPs or T3 administration individually, markedly alleviated disease development, enhanced oligodendrocyte survival, inhibited myelin damage, and promoted myelin regeneration in the lesions of experimental autoimmune encephalomyelitis mice. Taken together, our findings showed that engineered EVPs possess a remarkable CNS lesion targeting potential that offers a potent therapeutic strategy for CNS demyelinating diseases as well as neuroinflammation.

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