Peripheral artery disease is a cardiovascular disease characterized by a narrowing of arteries that supply blood to the extremities, particularly, the legs. When surgical intervention is warranted, the primary approach is balloon angioplasty. Drug coated balloons (DCB) designed to release antimitogenic agents to the site of the blockage are a relatively new product aimed at reducing artery re-narrowing, or restenosis, after intervention. However, first generation DCB utilize mainly direct application of the chemotherapy drug paclitaxel, along with hydrophilic excipients to facilitate uptake into the tissue, and the majority of drug is released from the DCB systemically. We thus designed a drug-eluting nanoparticle delivery system for firm attachment to the balloon surface and only slow release of its entrapped drugs within a fluid environment. We furthermore chose the relatively nontoxic polyphenols resveratrol and quercetin as active agents we've shown reduce smooth muscle cell proliferation and inflammatory cell and platelet activation, all contributing events in restenosis. A polymeric nanoparticle (pNP) system based on poly(lactic-co-glycolic) acid but possessing a positive charge was designed for firm attachment to the balloon matrix, followed by adhesion to the negatively charged bilayer of the vascular wall. As a first step toward testing its biologic properties, drug elution into a simulated blood fluid was determined, as well as the fold enrichment of cells with drug after exposure to the drug-entrapped pNPs compared to drugs only. Cytotoxicity to vascular smooth muscle cells was assessed, along with their biocompatibility, determined as their ability to promote red blood cell lysis. The drug-entrapped pNP system showed excellent biocompatibility with limited cytotoxicity. In addition, the pNPs released the two drugs only very slowly over 10 days. Development of a spray process for delivering the drug-entrapped pNPs to a balloon surface and in vivo testing in small animals appears warranted. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 00B: 000-000, 2018.