Traditional hapten-protein conjugate nicotine vaccines have shown less than desired immunological efficacy due to their poor recognition and internalization by immune cells. We developed a novel lipid-polymeric hybrid nanoparticle-based nicotine vaccine to enhance the immunogenicity of the conjugate vaccine, and studied the influence of particle size on its immunogenicity and pharmacokinetic efficacy. The results demonstrated that the nanovaccines, regardless of size, could induce a significantly stronger immune response against nicotine compared to the conjugate vaccine. Particularly, a significantly higher anti-nicotine antibody titer was achieved by the 100 compared to the 500 nm nanovaccine. In addition, both the 100 and 500 nm nanovaccines reduced the distribution of nicotine into the brain significantly. The 100 nm nanovaccine exhibited better pharmacokinetic efficacy than the 500 nm nanovaccine in the presence of alum adjuvant. These results suggest that a lipid-polymeric nanoparticle-based nicotine vaccine is a promising candidate to treat nicotine dependence. (C) 2016 Elsevier Inc. All rights reserved.