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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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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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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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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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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DOI: https://doi.org/10.1038/s41565-024-01648-8