PROJECT SUMMARY Drug-coated balloons (DCBs) have evolved as a promising interventional strategy for peripheral arterial disease (PAD). While paclitaxel (PTX)-based DCBs were emerging as the interventional standard of care for many PAD lesions, a recent meta-analysis of randomized trials suggested excess late mortality in PTX-treated patients. This result prompted the FDA to issue a warning that ultimately led to a marked reduction of the clinical use of DCBs. This response by the clinical and regulatory communities underscores a need to develop next-generation DCBs that could show improved efficacy and safety profiles. Drawing from our previous experience related to studies on drug-eluting stents and more recently on DCBs, we propose two hypothesis- driven design strategies to enhance DCB performance and safety. Aims I and II will consider balloon surface hydrophilicity and coating composition, respectively, as critical DCB design variables, and seek to identify mechanistic relations between these design variables, coating microstructure, drug delivery efficacy, as well as local and systemic toxicity. We will predict optimal DCB designs for both acute and sustained drug delivery using a biophysical contact model that computes deterministic interfacial mechanical interactions during DCB deployment. Our material design space includes two excipients (urea and shellac) and two drugs (PTX and dexamethasone (DEX)), with consideration of variable excipient-drug ratios and novel balloon pre-treatment protocols prior to coating applications. We will use an in vivo model of rabbit atherosclerosis to evaluate optimized DCBs, providing support for our approach to enhance PTX delivery and insight into the clinical potential of DEX as an alternate DCB payload.