MicroRNA-145-loaded poly(lactic-co-glycolic acid) nanoparticles attenuate venous intimal hyperplasia in a rabbit model

Background: MicroRNA-145 (miR-145) reportedly alters the phenotype of vascular smooth muscle cells (VSMCs) from a proliferative to a contractile state. So far, viral or plasmid vectors have been experimentally used to transduce microRNAs into VSMCs. We hypothesized that a simple ex vivo microRNA delivery system using miR-145-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (PLGA NPs) could control the VSMC phenotype and prevent intimal hyperplasia. Methods: Jugular vein grafts of male Japanese white rabbits were soaked in phosphate-buffered saline, control microRNA (cont-miR)-loaded PLGA NP solution or miR-145-loaded PLGA NP solution for 30 minutes (n = 8 for each). Vein grafts were implanted in the ipsilateral carotid artery and assessed 2 weeks after the implantation. Results: Quantitative polymerase chain reaction analysis showed significantly higher miR-145 expression in the miR-145-treated group. The neointimal area was significantly smaller in the miR-145-treated group (phosphate-buffered saline-treated vs cont-miR-treated vs miR-145-treated group; 1.63 +/- 0.52 mm(2) vs 1.67 +/- 0.49 mm(2) vs 0.88 +/- 0.34 mm(2), respectively; P < .01 for the miR-145-treated vs the cont-miR-treated group). In the miR-145-treated group, Ki-67-positive cells were significantly fewer, indicating lower VSMC proliferation. An inflammation-related molecule, CD40 expression was significantly reduced by miR-145-loaded PLGA NP treatment. Conclusions: Local and sustained release of miR-145 by PLGA NPs attenuated intimal hyperplasia in the rabbit model by maintaining VSMCs in a contractile state. This simple ex vivo miR-145 delivery system would be promising toward broader clinical application.