Iron-oxide-based contrast agents for magnetic resonance imaging (MRI) had been clinically approved in the United States and Europe, yet most of these nanoparticle products were discontinued owing to failures to meet rigorous clinical requirements. Significant advances have been made in the synthesis of magnetic nanoparticles and their biomedical applications, but several major challenges remain for their clinical translation, in particular large-scale and reproducible synthesis, systematic toxicity assessment, and their preclinical evaluation in MRI of large animals. Here, we report the results of a toxicity study of iron oxide nanoclusters of uniform size in large animal models, including beagle dogs and the more clinically relevant macaques. We also show that iron oxide nanoclusters can be used as T 1 MRI contrast agents for high-resolution magnetic resonance angiography in beagle dogs and macaques, and that dynamic MRI enables the detection of cerebral ischaemia in these large animals. Iron oxide nanoclusters show clinical potential as next-generation MRI contrast agents.

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T.H. and S.H.C. acknowledge financial support from the Research Center Program of the Institute for Basic Science (IBS-R006-D1) in Korea. Y.L., D.-H.Z., D.L. and L.Z. acknowledge financial support from the National Key Research and Development Program of China (2016YFA0203600), National Natural Science Foundation of China (51572067, 21501039, 51503180, 31370983, 81401518, 31430028 and 5161101036), Fundamental Research Funds for the Central Universities (2015HGCH0009), Anhui Province Funds for Distinguished Young Scientists (1508085J08), Natural Science Foundation of Anhui Province (1708085ME114) and Young Top-Notch Talent Support Scheme at Anhui Medical University.

Author information

Author notes

  1. Yang Lu, Yun-Jun Xu, Guo-bing Zhang and Daishun Ling contributed equally to this work.


  1. Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul, 08826, Republic of Korea

    • Yang Lu
    • , Michael J. Hackett
    • , Byung Hyo Kim
    • , Hogeun Chang
    • , Jonghoon Kim
    • , Nohyun Lee
    • , Seung Hong Choi
    •  & Taeghwan Hyeon
  2. School of Chemical and Biological Engineering, and Institute of Chemical Processes, Seoul National University, Seoul, 08826, Republic of Korea

    • Yang Lu
    • , Michael J. Hackett
    • , Byung Hyo Kim
    • , Hogeun Chang
    • , Jonghoon Kim
    • , Nohyun Lee
    •  & Taeghwan Hyeon
  3. School of Chemistry and Chemical Engineering, Hefei University of Technology, Hefei, 230009, China

    • Yang Lu
    • , Ya-Dong Wu
    •  & Liang Dong
  4. Department of Radiology, Anhui Provincial Hospital, Hefei, 230001, China

    • Yun-Jun Xu
  5. The First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, 230022, China

    • Guo-bing Zhang
    • , Ming-quan Wang
    • , Li Zhang
    •  & Hui-Qin Wen
  6. Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China

    • Daishun Ling
    • , Fangyuan Li
    •  & Bo Yang
  7. Key Laboratory of Biomedical Engineering of the Ministry of Education, College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou, 310058, China

    • Daishun Ling
    •  & Fangyuan Li
  8. Department of Dental Implant Centre, Stomatologic Hospital and College, Anhui Medical University, Key Laboratory of Oral Diseases Research of Anhui Province, Hefei, 230032, China

    • Yong Zhou
    • , Tao Wu
    • , Jia-Cai He
    •  & Duo-Hong Zou
  9. Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China

    • Xin-Tian Hu
  10. School of Advanced Materials Engineering, Kookmin University, Seoul, 02727, Republic of Korea

    • Nohyun Lee
  11. Department of Radiology, Seoul National University Hospital, and the Institute of Radiation Medicine, Medical Research Center, Seoul National University, Seoul, 03080, Republic of Korea

    • Seung Hong Choi
  12. Second Dental Clinic, Ninth People’s Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai Key Laboratory of Stomatology, National Clinical Research Center of Stomatology, Shanghai, 200001, P. R. China

    • Duo-Hong Zou


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T.H., S.H.C., D.-H.Z., Y.L., D.L., Y.-J.X. and G.-b.Z. conceived the idea and designed the experiments. T.H., S.H.C. and D.-H.Z. supervised the research. Y.L., D.L., B.H.K., H.C., J.K. and N.L. processed the samples. D.-H.Z., T.W., Y.Z., J.-C.H. and L.Z. worked on the macaque breeding. G.-b.Z. and M.-q.W. worked on the cerebral ischaemia model. Y.-J.X., Y.L., D.L., N.L. and S.H.C. investigated the MR performance. T.W., Y.Z., L.Z. and H.-Q.W. processed the biocompatibility evaluation. Y.-D.W., L.D., F.L. and B.Y. performed the biodistribution and pharmacokinetic study in vivo. X.-T.H. performed the pathological analysis. Y.L., D.L., M.J.H., Y.-J.X., G.-b.Z., N.L., T.H., S.H.C. and D.-H.Z. wrote the paper. All authors analysed and discussed the results.

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The authors declare no competing financial interests.

Corresponding authors

Correspondence to Seung Hong Choi or Taeghwan Hyeon or Duo-Hong Zou.

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