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Vitamin lipid nanoparticles enable adoptive macrophage transfer for the treatment of multidrug-resistant bacterial sepsis

Nature Nanotechnology volume 15, pages 41–46 (2020)Cite this article

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Abstract

Sepsis, a condition caused by severe infections, affects more than 30 million people worldwide every year and remains the leading cause of death in hospitals1,2. Moreover, antimicrobial resistance has become an additional challenge in the treatment of sepsis3, and thus, alternative therapeutic approaches are urgently needed2,3. Here, we show that adoptive transfer of macrophages containing antimicrobial peptides linked to cathepsin B in the lysosomes (MACs) can be applied for the treatment of multidrug-resistant bacteria-induced sepsis in mice with immunosuppression. The MACs are constructed by transfection of vitamin C lipid nanoparticles that deliver antimicrobial peptide and cathepsin B (AMP-CatB) mRNA. The vitamin C lipid nanoparticles allow the specific accumulation of AMP-CatB in macrophage lysosomes, which is the key location for bactericidal activities. Our results demonstrate that adoptive MAC transfer leads to the elimination of multidrug-resistant bacteria, including Staphylococcus aureus and Escherichia coli, leading to the complete recovery of immunocompromised septic mice. Our work provides an alternative strategy for overcoming multidrug-resistant bacteria-induced sepsis and opens up possibilities for the development of nanoparticle-enabled cell therapy for infectious diseases.

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Fig. 1: Schematic illustration of adoptive macrophage transfer and chemical structures of the vitamin-derived lipids.
Fig. 2: Screening, optimization and characterization of VLNPs.
Fig. 3: Therapeutic effects of MAC-RAWs in MDRSA-induced sepsis mice with immunosuppression.
Fig. 4: Therapeutic effects of MAC-BMDMs in sepsis mice induced with mixed MDR bacteria (Staphylococcus aureus and E. coli) with immunosuppression.

Data availability

The data that support the plots within this paper and other findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We acknowledge the use of the core facility provided by the Campus Microscopy & Imaging Facility at Ohio State University. X.Z. acknowledges support from Fundamental Research Funds for the Central Universities (No. DUT18RC(3)027). Y.D. acknowledges support from National Institutes of Health (NIH) through the Maximizing Investigators’ Research Award R35GM119679 of the National Institute of General Medical Sciences as well as the start-up fund from the College of Pharmacy at Ohio State University.

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Author notes

  1. These authors contributed equally: Xucheng Hou, Xinfu Zhang.

Authors and Affiliations

  1. Division of Pharmaceutics & Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA

    Xucheng Hou, Xinfu Zhang, Weiyu Zhao, Chunxi Zeng, Shi Du, Chengxiang Zhang, Wenqing Li & Yizhou Dong

  2. State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian, China

    Xinfu Zhang

  3. Center for Electron Microscopy and Analysis, The Ohio State University, Columbus, OH, USA

    Binbin Deng & David W. McComb

  4. Department of Materials Science and Engineering, The Ohio State University, Columbus, OH, USA

    David W. McComb

  5. Department of Biomedical Engineering, Center for Clinical and Translational Science, Comprehensive Cancer Center, Dorothy M. Davis Heart & Lung Research Institute, Department of Radiation Oncology, The Ohio State University, Columbus, OH, USA

    Yizhou Dong

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  1. Xucheng Hou
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Contributions

X.H. and X.Z. conceived and designed the experiments. X.H. and X.Z. performed the experiments and wrote the paper. W.Z. contributed to animal and live-cell imaging. C. Zeng prepared the mRNA. B.D. and D.W.M. contributed to the Cryo-TEM imaging. S.D. and W.L. contributed to the animal experiments. C. Zhang contributed to flow cytometry assays. Y.D. conceived and supervised the project and wrote the paper. The final manuscript was edited and approved by all authors.

Corresponding author

Correspondence to Yizhou Dong.

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Peer review information Nature Nanotechnology thanks Timothy Foster, Anthony Gordon and Liangfang Zhang for their contribution to the peer review of this work.

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Supplementary Figures 1–10 and RNA sequences.

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Hou, X., Zhang, X., Zhao, W. et al. Vitamin lipid nanoparticles enable adoptive macrophage transfer for the treatment of multidrug-resistant bacterial sepsis. Nat. Nanotechnol. 15, 41–46 (2020). https://doi.org/10.1038/s41565-019-0600-1

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