Current pharmacological interventions for atherosclerotic cardiovascular disease primarily focus on risk mitigation but fall short of directly addressing underlying plaque-forming cells. While the common therapy approach has been to treat the inflammation observed in atherosclerotic cardiovascular disease, site- and cell-selective therapies that target the atherosclerotic plaques, but not the endothelium are currently not available.
Our researchers have developed a cell-selective therapy for atherosclerotic plaques, targeting the cells responsible for their formation while protecting the endothelium. To achieve this, they employed a self-replicating miRNA switch approach. The miRNA switch consists of a synthetic mRNA encoding the cell cycle inhibitor p27 with a complementary target site for the endothelial cell (EC)-specific miR-126. This allows for the selective expression of p27 in VSMCs and infiltrating immune cells, while protecting the endothelium. Using a cationic amphipathic cell-penetrating peptide as a delivery platform, the mRNA self-assembles with the p27 miRNA switch into compacted nanoparticles. This therapy has reduced plaque burden in animal models.
This targeted approach offers a therapeutic solution for various stenotic conditions, potentially reducing the need for stents. Its customization ability to selectively target cells in diverse diseases, including fibrotic conditions, and enable cell-specific gene editing represents a significant stride toward precision medicine.
Selective Inhibition of Vessel Re-narrowing Simultaneously promotes re-endothelialization and vessel healing: Outline of CVD therapeutics and Immunofluorescence confocal images of α-smooth muscle cell actin (αSMA) and endothelial cell coverage (CD31) of uninjured and wire injured femoral arteries of mice treated with control niRFP (n=5) or p27-miRNA switch nanoparticles (n=6) every 72 hours for 2 weeks after injury