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

John H. Lockhart, Jeffrey VanWye, Richa Banerjee, Samuel A. Wickline, Hua Pan, Hana Totary-Jain

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1744-1757
Number of pages14
JournalMolecular Therapy
Volume29
Issue number5
DOIs
StatePublished - May 5 2021

Keywords

  • atherosclerosis
  • cardiovascular disease
  • cell-selective therapy
  • endosomal escape
  • mRNA therapeutics
  • nanotherapy
  • restenosis

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