4.8 Article

Targeted delivery of neural progenitor cell-derived extracellular vesicles for anti-inflammation after cerebral ischemia

Journal

THERANOSTICS
Volume 11, Issue 13, Pages 6507-6521

Publisher

IVYSPRING INT PUBL
DOI: 10.7150/thno.56367

Keywords

extracellular vesicles; exosomes; anti-inflammation; targeted delivery; cerebral ischemia

Funding

  1. National Natural Science Foundation of China [81673416, 81972364, 81973308]
  2. Key R&D Program of Jiangsu Province [BE2016761, 2017CX010]
  3. Natural Science Foundation of Jiangsu Province [BK20170107, BK20180165]
  4. SEU-NJMU Joint Research Program [2242018K3DN24]
  5. Clinical Medical Expert Team Program of Suzhou [SZYJTD201725]

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Ischemic stroke is a major cause of death and anti-inflammatory strategies are promising for reducing brain injury during reperfusion. Stem cell-derived extracellular vesicles (EVs) have emerged as therapeutic agents for immune modulation. By attaching targeting ligands onto EVs using a recombinant fusion protein, researchers were able to deliver anti-inflammatory EVs to the ischemic brain, showing promising results in suppressing inflammation.
Ischemic stroke remains a major cause of death, and anti-inflammatory strategies hold great promise for preventing major brain injury during reperfusion. In the past decade, stem cell-derived extracellular vesicles (EVs) have emerged as novel therapeutic effectors in immune modulation. However, the intravenous delivery of EVs into the ischemic brain remains a challenge due to poor targeting of unmodified EVs, and the costs of large-scale production of stem cell-derived EVs hinder their clinical application. Methods: EVs were isolated from a human neural progenitor cell line, and their anti-inflammatory effects were verified in vitro. To attach targeting ligands onto EVs, we generated a recombinant fusion protein containing the arginine-glycine-aspartic acid (RGD)-4C peptide (ACDCRGDCFC) fused to the phosphatidylserine (PS)-binding domains of lactadherin (C1C2), which readily self-associates onto the EV membrane. Subsequently, in a middle cerebral artery occlusion (MCAO) mouse model, the RGD-C1C2-bound EVs (RGD-EV) were intravenously injected through the tail vein, followed by fluorescence imaging and assessment of proinflammatory cytokines expression and microglia activation. Results: The neural progenitor cell-derived EVs showed intrinsic anti-inflammatory activity. The RGD-EV targeted the lesion region of the ischemic brain after intravenous administration, and resulted in a strong suppression of the inflammatory response. Furthermore, RNA sequencing revealed a set of 7 miRNAs packaged in the EVs inhibited MAPK, an inflammation related pathway. Conclusion: These results point to a rapid and easy strategy to produce targeting EVs and suggest a potential therapeutic agent for ischemic stroke.

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