Cardiovascular diseases remain the leading cause of mortality worldwide, with percutaneous coronary interventions (PCI) using drug-eluting stents (DES) as the standard treatment for coronary artery disease. Despite advancements in DES technology, challenges such as restenosis and stent thrombosis still necessitate further interventions and carry considerable risks, highlighting an urgent need for a novel therapeutic approach with lower restenosis rates and reduced reintervention risks. Drug-eluting balloons (DEBs) coated with anti-proliferative agents offer a novel method of local drug delivery for reducing restenosis by directly administering drugs to the lesion site. However, efficient delivery of drugs within the brief procedural window while minimizing drug loss during maneuvering to the target site remains a challenge. Herein, we developed a pressure-responsive and pH-triggered, paclitaxel (PTX) coated DEB catheter for rapid and high-dose delivery of paclitaxel to the lesion sites, overcoming the limitations of drug dispersion and inefficiencies associated with conventional DEBs. Using the charge reversion of albumin around its isoelectric point, paclitaxel-loaded human serum albumin nanoparticles (PTX-HSA-NPs) and heparin were coated using a layer-by-layer deposition method at pH 4.0. Upon exposure to physiological pH (i.e., 7.4), the coating is rapidly released from the balloon surface. Combined with a protective shellac coating, the DEB achieved controlled release of high-dose paclitaxel to the arterial tissue in vivo (up to 400 µg per gram tissue), exceeding current DEBs in the clinic. These results suggest the pH-responsive, multi-layer coated DEB’s potential for superior procedural outcomes, addressing a critical unmet need in PCI.