Developing Therapeutically Enhanced Extracellular Vesicles for Atherosclerosis Therapy

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.