Autologous saphenous veins are the most frequently used conduits for coronary and peripheral artery bypass grafting. However, vein graft failure rates of 40-50% within 10 years of the implantation lead to poor long-term outcomes after bypass surgery. Currently, only a few therapeutic approaches for vein graft disease have been successfully translated into clinical practice. Building on the past two decades of advanced understanding of vein graft biology and the pathophysiological mechanisms underlying vein graft disease, nanomedicine-based strategies offer promising opportunities to address this important unmet clinical need. In this Review, we provide deep insight into the latest developments in the rational design and applications of nanoparticles that have the potential to target specific cells during various pathophysiological stages of vein graft disease, including early endothelial dysfunction, intermediate intimal hyperplasia and late-stage accelerated atherosclerosis. Additionally, we underscore the convergence of nanofabricated biomaterials, with a particular focus on hydrogels, external graft support devices and cell-based therapies, alongside bypass surgery to improve local delivery efficiency and therapeutic efficacy. Finally, we provide a specific discussion on the considerations, challenges and novel perspectives for the future clinical translation of nanomedicine for the treatment of vein graft disease.