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Neutrophil hitchhiking for drug delivery to the bone marrow

Nature Nanotechnology volume 18, pages 647–656 (2023)Cite this article

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Abstract

Pharmaceuticals have been developed for the treatment of a wide range of bone diseases and disorders, but suffer from problematic delivery to the bone marrow. Neutrophils are naturally trafficked to the bone marrow and can cross the bone marrow–blood barrier. Here we report the use of neutrophils for the targeted delivery of free drugs and drug nanoparticles to the bone marrow. We demonstrate how drug-loaded poly(lactic-co-glycolic acid) nanoparticles are taken up by neutrophils and are then transported across the bone marrow–blood barrier to boost drug concentrations in the bone marrow. We demonstrate application of this principle to two models. In a bone metastasis cancer model, neutrophil delivery is shown to deliver cabazitaxel and significantly inhibit tumour growth. In an induced osteoporosis model, neutrophil delivery of teriparatide is shown to significantly increase bone mineral density and alleviate osteoporosis indicators.

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Fig. 1: Neutrophil-based bone-marrow-targeted drug-delivery system actively delivers drugs into the bone marrow.
Fig. 2: Characterization of CTX-NPs and CTX-NPs@NEs.
Fig. 3: Biodistribution of NEs and NPs@NEs.
Fig. 4: Anti-tumour effect of CTX-NPs@NEs on bone metastasis of breast cancer.
Fig. 5: Impact of PTH-NPs@NEs on osteoporosis.
Fig. 6: Toxicity of the neutrophil-based bone-marrow-targeted drug-delivery system.

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Data availability

Data supporting the findings of this study are available within the Article and its Supplementary Information. All relevant data can be made available upon reasonable request to the corresponding authors. Source data are provided with this paper.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81973246 (J.Y.) and 82003667 (L.L.)). We thank J. Wang from the Core Facilities, Zhejiang University School of Medicine, X. Zhang from the Analysis Center of Agrobiology and Environmental Sciences and Institute of Agrobiology and Environmental Sciences, Zhejiang University, and G. Wang from the radiology department, the First Affiliated Hospital, Zhejiang University School of Medicine for technical support. We thank Servier Medical Art for support with figure drawing.

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Authors and Affiliations

  1. College of Pharmaceutical Sciences, Zhejiang University, Zhejiang, P. R. China

    Zhenyu Luo, Yichao Lu, Yingying Shi, Mengshi Jiang, Xinyu Shan, Xiang Li, Junlei Zhang, Bing Qin, Xu Liu, Xuemeng Guo, Jiaxin Huang, Yu Liu, Sijie Wang, Qingpo Li, Lihua Luo & Jian You

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  1. Zhenyu Luo
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Contributions

Z.L., L.L. and J.Y. designed the experiments, analysed the data and wrote the paper. Z.L. performed most of the experiments. Y.Lu., X.S., X.G. and Y.Liu assisted with animal experiments. Y.S., X.Li. and B.Q. assisted with cellular experiments. J.Z. and X.Liu. helped with data analysis. M.J., J.H. and S.W. revised the manuscript. Q.L., J.Y. and L.L. supervised the project.

Corresponding authors

Correspondence to Qingpo Li, Lihua Luo or Jian You.

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Nature Nanotechnology thanks Michael Mitchell and Sara Rankin for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–14.

Reporting Summary

Supplementary Video 1

PET/CT video of Free FDG at 2 h.

Supplementary Video 2

PET/CT video of Free FDG at 6 h.

Supplementary Video 3

PET/CT video of NEs (age: 6 h) at 2 h.

Supplementary Video 4

PET/CT video of NEs (age: 6 h) at 6 h.

Supplementary Video 5

PET/CT video of NEs (age: 24 h) at 2 h.

Supplementary Video 6

PET/CT video of NEs (age: 24 h) at 6 h.

Source data

Source Data Fig. 2

Main Fig. 2 statistical source data.

Source Data Fig. 3

Main Fig. 3 statistical source data.

Source Data Fig. 4

Main Fig. 4 statistical source data.

Source Data Fig. 5

Main Fig. 5 statistical source data.

Source Data Fig. 6

Main Fig. 6 statistical source data.

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Luo, Z., Lu, Y., Shi, Y. et al. Neutrophil hitchhiking for drug delivery to the bone marrow. Nat. Nanotechnol. 18, 647–656 (2023). https://doi.org/10.1038/s41565-023-01374-7

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