AbstractIntroductionStaphylococcus aureusseriously threatens human and animal health. IsdB137‐361of the iron surface determinant B protein (IsdB) fromS. aureusexhibits the strong immunogenicity, but its immunoprotective effect is still to be further promoted. Because PEI‐PLGA nanoparticles are generated by PEI conjugate with PLGA to develop great potential as a novel immune adjuvant, the immunogenicity of IsdB137‐361is likely be strengthened by PEI‐PLGA.MethodsHere, PEI‐PLGA nanoparticles containing IsdB137‐361proteins were prepared by optimizing the entrapment efficiency. Mice were immunized with IsdB137‐361‐PEI‐PLGA nanoparticles to assess their anti‐S. aureuseffects. The level of IFN‐γ, IL‐4, IL‐17, and IL‐10 cytokines from spleen lymphocytes in mice and generation of the antibodies against IsdB137‐361in serum was assessed by ELISA, the protective immune response was appraised byS. aureuschallenge.ResultsIsdB137‐361proteins loaded by PEI‐PLGA were able to stimulate effectively the proliferation of spleen lymphocytes and increase the secretion of IFN‐γ, IL‐4, IL‐17, and IL‐10 cytokine from spleen lymphocytes, and significantly enhance generation of the antibodies against IsdB137‐361in serum, reduce the level of bacterial load in liver, spleen and kidney, and greatly improve the survival rate of mice after challenge.ConclusionThese data showed that PEI‐PLGA nanoparticles can significantly enhance the immunogenicity of IsdB137‐361proteins, and provide an important reference for the development of novel immune adjuvant.