Despite the significant alleviation of clinical cardiovascular diseases through appropriate interventional treatments, the recurrence of vascular restenosis necessitating reoperation remains a substantial challenge impacting patient prognosis. Plant-derived exosome-like nanovesicles (PELNs) are integral to interspecies cellular communication, with their functions and potential applications garnering significant attention from the research community. This study extracted Solanum lycopersicum-derived exosome-like nanovesicles (SL-ELNs) and demonstrated their inhibition of PDGF-BB-induced proliferation, migration, and phenotypic transformation of vascular smooth muscle cells (VSMCs). Mechanistically, miRNA164a/b-5p within the SL-ELNs reduced the expression of Keap1 mRNA, thereby increasing nuclear translocation of Nrf2 and enhancing the expression of antioxidant genes to alleviate oxidative stress. In a mouse carotid artery injury model, it was further confirmed that miRNA164a/b-5p within the SL-ELNs could inhibit neointimal hyperplasia. These results suggest that SL-ELNs inhibit VSMCs proliferation, migration, and phenotypic transformation, and they might be potential therapeutic agents for the prevention or treatment of restenosis.