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Multimodal smart systems reprogramme macrophages and remove urate to treat gouty arthritis

Nature Nanotechnology (2024)Cite this article

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Abstract

Gouty arthritis is a chronic and progressive disease characterized by high urate levels in the joints and by an inflammatory immune microenvironment. Clinical data indicate that urate reduction therapy or anti-inflammatory therapy alone often fails to deliver satisfactory outcomes. Here we have developed a smart biomimetic nanosystem featuring a ‘shell’ composed of a fusion membrane derived from M2 macrophages and exosomes, which encapsulates liposomes loaded with a combination of uricase, platinum-in-hyaluronan/polydopamine nanozyme and resveratrol. The nanosystem targets inflamed joints and promotes the accumulation of anti-inflammatory macrophages locally, while the uricase and the nanozyme reduce the levels of urate within the joints. Additionally, site-directed near-infrared irradiation provides localized mild thermotherapy through the action of platinum and polydopamine, initiating heat-induced tissue repair. Combined use of these components synergistically enhances overall outcomes, resulting in faster recovery of the damaged joint tissue.

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Fig. 1: The nanocarrier used to treat GA.
Fig. 2: Characterization of PtHD.
Fig. 3: Characterization of D-N[EM2].
Fig. 4: Effects of D-N[EM2] on RAW 264.7 or HUVEC cells.
Fig. 5: Pharmacodynamics, pharmacokinetics and safety evaluation of D-N[EM2].
Fig. 6: Therapeutic mechanisms of D-N[EM2] for HUA and GA at molecular and protein levels.

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Data availability

The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD 051823. The raw data that support the graphs in Supplementary Figs. 28 and 31–38 are available in the Supplementary Data. Source data are provided with this paper.

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Acknowledgements

This research was supported by grants from the National Science Fund for Excellent Young Scholars (82022070, L.Z.), Chongqing Technology Innovation and Application Development Special Major Project (CSTB2023TIAD-STX0003, J.Z.), Chongqing Science and Technology Committee and Chongqing Education Committee (CSTB2022NSCQ-LZX0057, J.Z.), Chongqing Education Committee (cqmudstd202216, J.Z.; CYS21236, J.X.; CYS23358, J.Z.), CQMU Program for Youth Innovation in Future Medicine (W0153, J.Z.) and Foundation for Distinguished Professor of Chongqing Medical University (202024, J.Z.).

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  1. These authors contributed equally: Jingxin Xu, Mingjun Wu, Jie Yang, Dezhang Zhao.

Authors and Affiliations

  1. Chongqing Research Center for Pharmaceutical Engineering, College of Pharmacy, Chongqing Medical University, Chongqing, China

    Jingxin Xu, Jie Yang, Dezhang Zhao, Dan He, Yingju Liu, Xiong Yan & Jingqing Zhang

  2. Institute of Life Sciences, Chongqing Medical University, Chongqing, China

    Mingjun Wu

  3. Department of Thoracic Surgery, University-Town Hospital of Chongqing Medical University, Chongqing, China

    Yuying Liu & Qunyou Tan

  4. Taiji Group Co. Ltd, Chongqing, China

    Daojun Pu

  5. College of Polymer Science and Engineering; Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy; State Key Laboratory of Polymer Materials Engineering; West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China

    Ling Zhang

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Contributions

J.X., Q.T., L.Z. and J.Z. designed the experiments, analysed the data and wrote the paper. J.X., M.W., J.Y. and D.Z. performed most of the experiments. Yingju Liu, X.Y. and Yuying Liu assisted with animal and cellular experiments. D.H. and D.P. assisted with analysis experiments and data analysis. Q.T., L.Z. and J.Z. supervised the project.

Corresponding authors

Correspondence to Qunyou Tan, Ling Zhang or Jingqing Zhang.

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

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Supplementary information

Supplementary Information

Supplementary Figs. 1–42, Tables 1–8, Abbreviations, Discussion, Methods and References.

Reporting Summary

Supplementary Video 1

Gait video of sham at 6 h.

Supplementary Video 2

Gait video of MSU at 6 h.

Supplementary Video 3

Gait video of URI at 6 h.

Supplementary Video 4

Gait video of D-N[EM2] at 6 h.

Supplementary Video 5

Gait video of D-N[EM2] + SL at 6 h.

Supplementary Video 6

Gait video of D-N[EM2] + QL at 6 h.

Supplementary Data 1

P values of proteomics in Supplementary Figs. 28 and 31–38.

Source data

Source Data Fig. 3

Unmodified gels and haemolysis assay for Fig. 3d–g.

Source Data Fig. 6

Unmodified western blots for Fig. 6f.

Source Data Fig. 6

P values of proteomics in Fig. 6e,g,h.

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Xu, J., Wu, M., Yang, J. et al. Multimodal smart systems reprogramme macrophages and remove urate to treat gouty arthritis. Nat. Nanotechnol. (2024). https://doi.org/10.1038/s41565-024-01715-0

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