Vaccines offer prophylactic treatments against atherosclerosis by eliciting effector T cell and antibody responses, which require effective delivery of antigen and adjuvant to activate dendritic cells (DC). Here we show that individual conjugation of antigen p210 and adjuvant CpG oligodeoxynucleotides onto superparamagnetic iron oxide nanoparticles formulates a nanovaccine cocktail that activates DCs for antigen cross-presentation and induction of co-stimulatory signals, cytokines and CD8+ effector/effector memory T cell responses. This nanovaccine modulates the DCs in the draining lymph nodes, activates both CD4+ and CD8+ T cells, elicits memory responses, and induces both anti-p210 IgM and IgG antibodies to suppress atherosclerosis. Lastly, three intradermal vaccinations of this nanovaccine mitigate the atherosclerosis development in the ApoE−/− mice. Our nanovaccine design and preclinical data thus presents a potential candidate for prophylactic treatment for atherosclerosis. Vaccination is a potential prophylactic treatment for atherosclerosis, but vaccine formulation and regime remain to be optimized. Here the authors show, in preclinical mouse models, that vaccination with nanovaccine containing the antigen, p210, and the adjuvant, CpG, conjugated on distinct carriers reaches better efficacy than co-conjugation.