For effective treatment of restenosis, therapeutic genes are delivered locally from a coated stent at the site of injury, leading to inhibition of smooth muscle proliferation and neo-intimal hyperplasia while promoting re-endothelialization. In a previous study, we delivered Akt1 siRNA nanoparticles (ASNs) from a hyaluronic acid (HA)-coated stent surface to specifically suppress the pro-proliferative Akt1 protein in smooth muscle cells (SMCs). In the present study, therapeutic efficacy was investigated in a rabbit restenosis model after percutaneous implantation of an ASN-immobilized stent in a rabbit iliac artery. Quantitative and qualitative analyses of in-stent restenosis were investigated in an in vivo animal model by micro-CT imaging and SEM observation, respectively. Proliferation status and neo-intima formation of the vascular tissues located near ASN-immobilized stents were analyzed by immunohistochemical staining using anti-Akt1 and anti-Ki67 antibodies and histological analyses, such as hematoxylin and eosin staining and Verhoeff's elastic stain. Re-endothelialization after implantation of an ASN-immobilized stent was also analyzed via immunohistochemistry using an anti-CD31 antibody. To elucidate the molecular mechanism related to reducing SMC proliferation and subsequent inhibition of in-stent restenosis in vivo, protein and mRNA expression of Akt1 and downstream signaling proteins were analyzed after isolating SMC-rich samples from the treated vasculature. The implanted Akt1 siRNA-eluting stent efficiently mitigated in-stent restenosis without any side effects and can be considered a successful substitute to current drug-eluting stents.