['Ultrasound-targeted microbubble destruction (UTMD) has proved to be a promising method for gene delivery. However, the feasibility and efficacy of UTMD-mediated gene delivery to the heart of large animals remain unclear. The present study was to explore the probability of increasing the transfection of microRNA-21 (miR-21) in swine heart by UTMD, and to search for the most suitable transfection conditions.', 'We first optimized ultrasound intensity for successful miR-21 delivery. After intravenous injection of miR-21/microbubble mixture (miR-21/MB), transthoracic ultrasound irradiation (US) was applied from the left anterior chest using different intensities (1, 2, and 3 W/cm(2)). Then the efficacy of UTMD-mediated miR-21 delivery into myocardium via intracoronary injection was explored. Solution of miR-21/MB was infused intravenously or intracoronarily with US over the heart. Swine undergoing phosphate-buffered saline (PBS) injection, miR-21/MB injection via ear vein or coronary artery without US served as the control. The dynamic changes of left ventricular ejection fraction (LVEF) and serum troponin I (cTnI) after UTMD were detected, then the left ventricular myocardium was harvested for hematoxylin and eosin (H&E) staining 4 days later; the expression levels of miR-21 and programmed cell death 4 (PDCD4) were detected by quantitative real time polymerase chain reaction (qRT-PCR) and Western blot, respectively.', 'Results showed that pulse ultrasound at an intensity of 2 W/cm(2) and a 50% duty ratio for 20 minutes, there was no increase in serum cTnI, no histological sign of myocardial damage, and no noted cardiac dysfunction with relatively higher miR-21 expression (P < 0.05). Compared to miR-21/MB alone, UTMD significantly increased gene expression in myocardium regardless of the delivery routes (P < 0.05). Interestingly, the transfection efficiency was found to be a little bit higher with intracoronary injection than that with intravenous injection, though the dose for intracoronary injection was half of the intravenous injection (P < 0.05).'] Does ultrasound-Targeted Microbubble Destruction enhance Gene Expression of microRNA-21 in Swine Heart via Intracoronary Delivery?