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Multimodal nanoimmunotherapy engages neutrophils to eliminate Staphylococcus aureus infections

Nature Nanotechnology (2024)Cite this article

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Abstract

The increasing prevalence of antimicrobial resistance in Staphylococcus aureus necessitates alternative therapeutic approaches. Neutrophils play a crucial role in the fight against S. aureus but suffer from deficiencies in function leading to increased infection. Here we report a nanoparticle-mediated immunotherapy aimed at potentiating neutrophils to eliminate S. aureus. The nanoparticles consist of naftifine, haemoglobin (Hb) and a red blood cell membrane coating. Naftifine disrupts staphyloxanthin biosynthesis, Hb reduces bacterial hydrogen sulfide levels and the red blood cell membrane modifies bacterial lipid composition. Collectively, the nanoparticles can sensitize S. aureus to host oxidant killing. Furthermore, in the infectious microenvironment, Hb triggers lipid peroxidation in S. aureus, promoting neutrophil chemotaxis. Oxygen supplied by Hb can also significantly enhance the bactericidal capability of the recruited neutrophils by restoring neutrophil respiratory burst via hypoxia relief. This multimodal nanoimmunotherapy demonstrates excellent therapeutic efficacy in treating antimicrobial-resistant S. aureus persisters, biofilms and S. aureus-induced infection in mice.

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Fig. 1: The design and characterization of Hb-Naf@RBCM NPs for treating S. aureus infection.
Fig. 2: In vitro antibacterial efficacy of Hb-Naf@RBCM NPs against S. aureus planktons, persisters and biofilms.
Fig. 3: Hb-Naf@RBCM NP-induced lipid peroxidation in S. aureus for neutrophil chemotaxis.
Fig. 4: Enhanced in vitro antimicrobial efficacy of neutrophils in a hypoxic microenvironment by Hb-Naf@RBCM NPs.
Fig. 5: In vivo therapeutic efficacy of Hb-Naf@RBCM NPs in mice with MRSA thigh infection and MRSA pneumonia.
Fig. 6: In vivo therapeutic efficacy of Hb-Naf@RBCM NPs in mice with MRSA peritonitis and MDRSA bacteraemia.

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Data availability

The data supporting the findings of this study are available within the article and its Supplementary Information.

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Acknowledgements

We acknowledge financial support from the National Institutes of Health (R21AI156253 and R01AI177173 to S.G.), an Advancing Vision Science Professorship from the University of Wisconsin–Madison, the Retina Research Foundation Edwin and Dorothy Gamewell Professorship, and the Wisconsin Institute for Discovery. We thank J. Handelsman for her help with this work. Figures 1a–d, 2a,e,i, 3e, 5a,g and 6a,e were created with BioRender.com (agreement number NJ26II9FBU).

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Authors and Affiliations

  1. Department of Ophthalmology and Visual Sciences, University of Wisconsin–Madison, Madison, WI, USA

    Jingcheng Zhu, Ruosen Xie, Ruixuan Gao, Yi Zhao, Nisakorn Yodsanit, Min Zhu, Jacobus C. Burger, Mingzhou Ye, Yao Tong & Shaoqin Gong

  2. Wisconsin Institute for Discovery, University of Wisconsin–Madison, Madison, WI, USA

    Jingcheng Zhu, Ruosen Xie, Ruixuan Gao, Yi Zhao, Nisakorn Yodsanit, Min Zhu, Jacobus C. Burger, Mingzhou Ye, Yao Tong & Shaoqin Gong

  3. Department of Biomedical Engineering, University of Wisconsin–Madison, Madison, WI, USA

    Jingcheng Zhu, Ruosen Xie, Ruixuan Gao, Yi Zhao, Nisakorn Yodsanit, Jacobus C. Burger, Mingzhou Ye, Yao Tong & Shaoqin Gong

  4. McPherson Eye Research Institute, University of Wisconsin–Madison, Madison, Wisconsin, USA

    Ruosen Xie & Shaoqin Gong

  5. Department of Chemistry, University of Wisconsin–Madison, Madison, WI, USA

    Min Zhu & Shaoqin Gong

  6. Department of Materials Science and Engineering, University of Wisconsin–Madison, Madison, WI, USA

    Shaoqin Gong

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Contributions

J.Z. and S.G. conceived the project and designed the experiments. J.Z., R.G., Y.Z., N.Y., M.Z., J.C.B, M.Y. and Y.T. performed experiments and analysed the data. R.X., Y.Z., N.Y., M.Z., M.Y. and Y.T. provided technical input on this project. J.Z., R.X. and S.G. drafted the paper. S.G. supervised the project.

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Correspondence to Shaoqin Gong.

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Competing interests

J.Z. and S.G. are inventors of a pending patent application filed by the Wisconsin Alumni Research Foundation. The other authors declare no competing interests.

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Nature Nanotechnology thanks Keira Melican and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary Methods, Figs. 1–22 and Table 1.

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Zhu, J., Xie, R., Gao, R. et al. Multimodal nanoimmunotherapy engages neutrophils to eliminate Staphylococcus aureus infections. Nat. Nanotechnol. (2024). https://doi.org/10.1038/s41565-024-01648-8

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