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Developing Therapeutically Enhanced Extracellular Vesicles for Atherosclerosis Therapy.

Neil Patel1, Elijah Avery1, Yi Huang1

  • 1Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA.

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Engineered extracellular vesicles (EVs) loaded with microRNA-145 (miR-145) effectively reduced atherosclerosis plaque burden in mice. These biologically-derived nanoparticles offer a promising alternative to synthetic carriers for treating cardiovascular disease.

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Area of Science:

  • Cardiovascular Research
  • Nanomedicine
  • Molecular Biology

Background:

  • Atherosclerosis is a leading global cause of death, with statin therapy having limitations.
  • Synthetic nanoparticles for drug delivery, like those used for microRNA-145 (miR-145) in previous studies, can cause immunogenic responses and have low efficiency for chronic diseases.
  • There is a need for improved therapeutic strategies to mitigate atherosclerosis progression.

Purpose of the Study:

  • To engineer extracellular vesicles (EVs) as a biologically-derived nanoparticle system for delivering miR-145 to inhibit atherosclerosis.
  • To enhance EV targeting to pathogenic vascular smooth muscle cells (VSMCs) using a monocyte chemoattractant protein 1 (MCP-1) peptide.
  • To evaluate the therapeutic efficacy of engineered EVs in vitro and in vivo models of atherosclerosis.

Main Methods:

  • Engineered EVs by loading miR-145 using ExoMotifs and functionalizing with MCP-1 peptide for targeted delivery to VSMCs expressing C-C chemokine receptor 2.
  • Assessed the restoration of VSMC gene expression and function in vitro using MCP-1-miR-145 EVs.
  • Evaluated plaque growth inhibition in ApoE-/- atherosclerotic mice treated with MCP-1-miR-145 EVs compared to synthetic nanoparticles.

Main Results:

  • MCP-1-miR-145 EVs restored VSMC gene expression and function in vitro.
  • Engineered EVs achieved similar therapeutic effects as synthetic nanoparticles but with a 25,000-fold lower dose of miR-145.
  • MCP-1-miR-145 EVs significantly inhibited plaque growth in mice at a 5000-fold lower miR-145 dose compared to synthetic nanoparticles.

Conclusions:

  • Therapeutically enhanced extracellular vesicles loaded with miR-145 represent a potent and efficient delivery system for atherosclerosis treatment.
  • This biologically-derived nanoparticle approach mitigates the drawbacks of synthetic nanoparticles, offering improved safety and efficacy.
  • Genetically engineered EVs show significant potential for reducing atherosclerosis plaque burden with substantially lower therapeutic cargo.