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Ceria-vesicle nanohybrid therapeutic for modulation of innate and adaptive immunity in a collagen-induced arthritis model

Nature Nanotechnology volume 18, pages 1502–1514 (2023)Cite this article

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A Publisher Correction to this article was published on 17 November 2023

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Abstract

Commencing with the breakdown of immune tolerance, multiple pathogenic factors, including synovial inflammation and harmful cytokines, are conjointly involved in the progression of rheumatoid arthritis. Intervening to mitigate some of these factors can bring a short-term therapeutic effect, but other unresolved factors will continue to aggravate the disease. Here we developed a ceria nanoparticle-immobilized mesenchymal stem cell nanovesicle hybrid system to address multiple factors in rheumatoid arthritis. Each component of this nanohybrid works individually and also synergistically, resulting in comprehensive treatment. Alleviation of inflammation and modulation of the tissue environment into an immunotolerant-favourable state are combined to recover the immune system by bridging innate and adaptive immunity. The therapy is shown to successfully treat and prevent rheumatoid arthritis by relieving the main symptoms and also by restoring the immune system through the induction of regulatory T cells in a mouse model of collagen-induced arthritis.

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Fig. 1: Design, fabrication and characterization of Ce-MSCNVs.
Fig. 2: Anti-inflammatory and immunomodulatory effect of Ce-MSCNVs in macrophages (M1-to-M2 polarization) and the consequent chondroprotection in vitro.
Fig. 3: Immunomodulatory effect of Ce-MSCNVs on DCs and the resultant induction of Treg cells in vitro.
Fig. 4: In vivo therapeutic effect of Ce-MSCNVs after intra-articular injection.
Fig. 5: Immune restoration by Ce-MSCNVs via Treg cell induction and rebalance of TH17/Treg cell ratio.
Fig. 6: Prophylactic effect of Ce-MSCNVs.

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Data availability

The data that support the findings of this study are available within the paper and the Supplementary Information. Source data are available for Figs. 1–6 and Supplementary Figs. 1, 3, 5–16, 20–23, 25–33, 35 and 36 in the associated source data file. Additional materials from this study are available from the corresponding author on reasonable request. Source data are provided with this paper.

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Acknowledgements

This work was supported by the Institute for Basic Science (IBS-R006-D1) (S.K. and T.H.), a Korean Fund for Regenerative Medicine (KFRM) grant funded by the Korean government (the Ministry of Science and ICT, the Ministry of Health & Welfare) (21A0504L1-11) (T.H.K., S.Y.J., S.Y., J.Y. and Y.J), and a National Research Foundation of Korea (NRF) grant funded by the Korean government (2019M3A9H1103651) (H.S.S., C.K. and B.-S.K.).

Author information

Author notes

  1. These authors contributed equally: Sagang Koo, Hee Su Sohn, Tae Hee Kim.

Authors and Affiliations

  1. Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul, Republic of Korea

    Sagang Koo, Boomin Choi, Ok Kyu Park, Min Soh & Taeghwan Hyeon

  2. School of Chemical and Biological Engineering, and Institute of Chemical Processes, Seoul National University, Seoul, Republic of Korea

    Sagang Koo, Hee Su Sohn, Cheesue Kim, Byung-Soo Kim & Taeghwan Hyeon

  3. Center for Biomaterials, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea

    Tae Hee Kim, Siyeon Yang, Se Youn Jang, Seongryeol Ye, Jin Yoo & Youngmee Jung

  4. Department of Fusion Research and Collaboration, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea

    Tae Hee Kim

  5. Animal Research Laboratory, Institute Pasteur Korea, Seongnam, Republic of Korea

    Siyeon Yang

  6. Department of Dentistry, Graduate School, Kyung Hee University, Seoul, Korea

    Se Youn Jang

  7. Program in Nanoscience and Technology, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea

    Seongryeol Ye

  8. Wide River Institute of Immunology, Seoul National University, Hongcheon, Republic of Korea

    Soo Hyeon Kim, Kyoung Sun Park & Hyun Mu Shin

  9. Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea

    Hyun Mu Shin

  10. BK21 FOUR Biomedical Science Project, Seoul National University College of Medicine, Seoul, Republic of Korea

    Hyun Mu Shin

  11. Center for Systems Biology, Massachusetts General Hospital Research Institute, Boston, MA, USA

    Mikyung Kang

  12. Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Mikyung Kang

  13. Department of Bionano Engineering and Bionanotechnology, Hanyang University, Ansan, Republic of Korea

    Dokyoon Kim

  14. School of Advanced Materials Engineering, Kookmin University, Seoul, Republic of Korea

    Nohyun Lee

  15. Interdisciplinary Program for Bioengineering, Institute of Engineering Research, Seoul National University, Seoul, Republic of Korea

    Byung-Soo Kim

  16. School of Electrical and Electronic Engineering, YU-KIST Institute, Yonsei University, Seoul, Republic of Korea

    Youngmee Jung

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  1. Sagang Koo
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Contributions

S.K., H.S.S. and T.H.K. conceived and designed the project. S.K., H.S.S., T.H.K., S. Yang, S.Y.J., S. Ye. and S.H.K. performed the experiments and analysed the data. B.C., K.S.P., H.M.S., O.K.P., C.K., M.K., M.S., J.Y., D.K. and N.L. provided technical input on this project. S.K., H.S.S., T.H.K., D.K., B.-S.K., Y.J. and T.H. wrote the manuscript. B.-S.K., Y.J. and T.H. supervised the overall research.

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Correspondence to Byung-Soo Kim, Youngmee Jung or Taeghwan Hyeon.

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Nature Nanotechnology thanks Liangfang Zhang, Mauro Perretti, and the other, anonymous, reviewer for their contribution to the peer review of this work.

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Supplementary Information

Supplementary Discussion, Figs. 1–36, unprocessed gel images for supplementary figures, gating strategy for flow cytometry, and references.

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Supplementary data 1

Sequences of primers for PCR analysis.

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Source Data Fig. 1k

Unprocessed western blots

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Koo, S., Sohn, H.S., Kim, T.H. et al. Ceria-vesicle nanohybrid therapeutic for modulation of innate and adaptive immunity in a collagen-induced arthritis model. Nat. Nanotechnol. 18, 1502–1514 (2023). https://doi.org/10.1038/s41565-023-01523-y

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