Self-assembled miRNA-switch nanoparticles target denuded regions and prevent restenosis

Mol Ther. 2021 May 5;29(5):1744-1757. doi: 10.1016/j.ymthe.2021.01.032. Epub 2021 Feb 3.


Cardiovascular disease is the leading cause of death and disability worldwide. Effective delivery of cell-selective therapies that target atherosclerotic plaques and neointimal growth while sparing the endothelium remains the Achilles heel of percutaneous interventions. The current study utilizes synthetic microRNA switch therapy that self-assembles to form a compacted, nuclease-resistant nanoparticle <200 nM in size when mixed with cationic amphipathic cell-penetrating peptide (p5RHH). These nanoparticles possess intrinsic endosomolytic activity that requires endosomal acidification. When administered in a femoral artery wire injury mouse model in vivo, the mRNA-p5RHH nanoparticles deliver their payload specifically to the regions of endothelial denudation and not to the lungs, liver, kidney, or spleen. Moreover, repeated administration of nanoparticles containing a microRNA switch, consisting of synthetically modified mRNA encoding for the cyclin-dependent kinase inhibitor p27Kip1 that contains one complementary target sequence of the endothelial cell-specific miR-126 at its 5' UTR, drastically reduced neointima formation after wire injury and allowed for vessel reendothelialization. This cell-selective nanotherapy is a valuable tool that has the potential to advance the fight against neointimal hyperplasia and atherosclerosis.

Keywords: atherosclerosis; cardiovascular disease; cell-selective therapy; endosomal escape; mRNA therapeutics; nanotherapy; restenosis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Atherosclerosis / etiology
  • Atherosclerosis / prevention & control*
  • Cell-Penetrating Peptides / administration & dosage*
  • Cell-Penetrating Peptides / pharmacology
  • Coronary Restenosis
  • Cyclin-Dependent Kinase Inhibitor p27 / antagonists & inhibitors*
  • Disease Models, Animal
  • Femoral Artery / injuries*
  • Mice
  • MicroRNAs / administration & dosage*
  • MicroRNAs / antagonists & inhibitors
  • MicroRNAs / genetics
  • Nanoparticles
  • Particle Size
  • Synthetic Biology


  • Cdkn1b protein, mouse
  • Cell-Penetrating Peptides
  • MIRN126 microRNA, mouse
  • MicroRNAs
  • Cyclin-Dependent Kinase Inhibitor p27