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Treatment of infarcted heart tissue via the capture and local delivery of circulating exosomes through antibody-conjugated magnetic nanoparticles

Nature Biomedical Engineering volume 4, pages 1063–1075 (2020)Cite this article

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Abstract

The systemic biodistribution of endogenous extracellular vesicles is central to the maintenance of tissue homeostasis. Here, we show that angiogenesis and heart function in infarcted heart tissue can be ameliorated by the local accumulation of exosomes collected from circulation using magnetic nanoparticles. The nanoparticles consist of a Fe3O4 core and a silica shell that is decorated with poly (ethylene glycol) conjugated through hydrazone bonds to two types of antibody, which bind either to CD63 antigens on the surface of extracellular vesicles or to myosin-light-chain surface markers on injured cardiomyocytes. On application of a local magnetic field, accumulation of the nanoparticles and cleavage of the hydrazone bonds under the acidic pH of injured cardiac tissue lead to the local release of the captured exosomes. In rabbit and rat models of myocardial infarction, the magnetic-guided accumulation of captured CD63-expressing exosomes in infarcted tissue led to reductions in infarct size as well as improved left-ventricle ejection fraction and angiogenesis. The approach could be used to manipulate endogenous exosome biodistribution for the treatment of other diseases.

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Fig. 1: Schematic of the vesicle-shuttle approach.
Fig. 2: Synthesis of GMNPs and their characterization.
Fig. 3: Fabrication and in vitro biofunction of the GMNPEC nanoparticles.
Fig. 4: Dual-targeting ability of GMNPEC in vitro and in vivo.
Fig. 5: Exosome-release characteristics of GMNPEC nanoparticles in vitro and in vivo.
Fig. 6: Injection of GMNPEC improves cardiac functions after MI.
Fig. 7: Systemic injection of GMNPEC improves cardiac functions in a rabbit MI model.

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Data availability

The main data supporting the results of this study are available within the paper and its Supplementary Information. The data used to make the graphs are provided as Supplementary Information. The raw and analysed datasets generated during the study are too large to be publicly shared, yet they are available for research purposes from the corresponding authors on reasonable request.

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Acknowledgements

This work was supported by the National Key Research and Development Program of China (no. 2016YFC1101400 to Y.J.), the National Natural Science Foundation of China (no. 81601606 to X.C. and no. 31670995 to S.L.), the Young Elite Scientist Sponsorship Program by CAST (no. 2017QNRC001 to S.L.), the Fundamental Research Funds for the Central Universities (no. 2016qngz02 to X.C.), the National Natural Science Foundation of Shaanxi Province (no. 2017JM5023 to X.C.), the open fund of the State Key Laboratory of Military Stomatology (no. 2017KA02 to X.C.) and the ARC Centre of Excellence in Convergent Bio-Nano Science and Technology (no. CE140100036 to J.J.G.), and the ARC Laureate Fellowship (no. FL150100060 to J.J.G.).

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  1. These authors contributed equally: Shiyu Liu, Xin Chen, Lili Bao, Tao Liu.

Authors and Affiliations

  1. State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Oral Diseases, Center for Tissue Engineering, Fourth Military Medical University, Xi’an, China

    Shiyu Liu, Lili Bao, Xiaoshan Yang, Xinyu Qiu & Yan Jin

  2. Cardiovascular Research Center, Center for Tissue Engineering, Fourth Military Medical University, Xi’an, China

    Shiyu Liu, Lili Bao, Xiaoshan Yang, Xinyu Qiu, Jiajia Xiao, Fengxing Pu & Yan Jin

  3. School of Chemical Engineering and Technology, Shaanxi Key Laboratory of Energy Chemical Process Intensification, Institute of Polymer Science in Chemical Engineering, Xi’an Jiao Tong University, Xi’an, China

    Xin Chen, Tao Liu, Pingyun Yuan & Yongkang Bai

  4. School of Chemistry, Australian Centre for NanoMedicine and ARC Australian Centre of Excellence in Convergent Bio-Nano Science and Technology, University of New South Wales, Sydney, New South Wales, Australia

    J. Justin Gooding

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Contributions

S.L., X.C., L.B. and T.L. contributed to the study design, data acquisition and interpretation. P.Y. and Y.B. characterized the properties of magnetic nanoparticles. X.Y. and X.Q. contributed to data analysis and interpretation. J.X. and F.P. performed the animal experiments. J.J.G. refined the manuscript. S.L., X.C. and Y.J. developed the concept and supervised experiments. All of the authors contributed to writing the manuscript.

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Correspondence to Xin Chen or Yan Jin.

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Liu, S., Chen, X., Bao, L. et al. Treatment of infarcted heart tissue via the capture and local delivery of circulating exosomes through antibody-conjugated magnetic nanoparticles. Nat Biomed Eng 4, 1063–1075 (2020). https://doi.org/10.1038/s41551-020-00637-1

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