USF researchers have developed misiRNA, a dual‑action mRNA, 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. p27 misiRNA: (i) selectively expresses p27 to inhibit vascular smooth muscle cell (VSMC) proliferation while sparing endothelial cells via a miR‑126–based switch, and (ii) reduces IL‑1β–driven inflammation through an integrated siRNA element. Using a cationic amphipathic cell-penetrating peptide, the mRNA self-assembles with the p27 miRNA switch into compacted nanoparticles that preferentially localize to diseased vasculature.
The p27 misiRNA construct shows cell‑selective activity in vitro, with miR‑126–guided restriction of p27 expression to VSMCs, resulting in selective anti‑proliferation and concurrent IL1B transcript and pro‑IL‑1β protein reduction via its integrated siRNA element. In ApoE‑/‑ mice, systemic delivery of p5RHH–misiRNA nanoparticles leads to localization within plaques and a significant reduction in aortic root plaque burden, demonstrating in‑vivo disease‑modifying efficacy.