Objectives: The aim of this study is to improve local-drug delivery efficiency and tissue absorption using the ultrasound (US)-responsible drug coating based on a newly developed US-controlled paclitaxel release balloon. Background: Low availability of the drug coating remains a major concern of the current drug coated balloon (DCB). The goal of this study is to develop a method to use an US-responsible paclitaxel-loaded microcapsules (PM) as the main content of balloon drug coating to enhance bioavailability of DCB. Methods: An US-controlled paclitaxel release balloon is designed and fabricated based on the US-responsible paclitaxel-loaded poly (lactic-co-glycolic acid) (PLGA) microcapsules. Rapid exchange percutaneous transluminal coronary angioplasty (PTCA) balloon catheters were coated with the PM. The deployment processes of the paclitaxel-loaded microcapsules coated balloons (PMCB) under US, PMCB without US and a homogenous matrix of paclitaxel and iopromide coated balloon (PICB) were then placed in healthy and stent implanted porcine coronary arteries. Results: In vitro release assay demonstrated an ability of US (1 MHz, 1.22 W/cm 2 , 1 minute) to affect the release kinetics of paclitaxel from PM by inducing a 76 ± 5.4% increase in the rate of release. The paclitaxel content in target vessels are 203 ± 37 μg/g for PMCB under US, 85 ± 23 μg/g for PMCB without US, and 107 ± 31 μg/g for PICB 1-hr post-surgery. The availability of the drug for the PMCB reaches 27% under US. Conclusions: The US-controlled paclitaxel release balloon significantly improved the drug content of the target vessels in the porcine model. K E Y W O R D S controlled drug release, drug coated balloon, paclitaxel, pharmacokinetics, PLGA microcapsules, US 1 | INTRODUCTION In recent decades, the outcomes of coronary heart disease (CHD) have markedly improved, which can be partly attributed to the evolution of percutaneous coronary intervention (PCI). From percutaneous transluminal coronary angioplasty to bare-metal stent and then to drugeluting stent, every step of PCI is attractive to interventional cardiologist, great progress has been made for patients with CHD. Drug eluting stent (DES) implantation is the first choice of treatment in PCI. The dramatic ability of DES to inhibit neointimal hyperplasia through