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Self-assembled RNA-triple-helix hydrogel scaffold for microRNA modulation in the tumour microenvironment

Nature Materials volume 15, pages 353–363 (2016)Cite this article

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Abstract

The therapeutic potential of miRNA (miR) in cancer is limited by the lack of efficient delivery vehicles. Here, we show that a self-assembled dual-colour RNA-triple-helix structure comprising two miRNAs—a miR mimic (tumour suppressor miRNA) and an antagomiR (oncomiR inhibitor)—provides outstanding capability to synergistically abrogate tumours. Conjugation of RNA triple helices to dendrimers allows the formation of stable triplex nanoparticles, which form an RNA-triple-helix adhesive scaffold upon interaction with dextran aldehyde, the latter able to chemically interact and adhere to natural tissue amines in the tumour. We also show that the self-assembled RNA-triple-helix conjugates remain functional in vitro and in vivo, and that they lead to nearly 90% levels of tumour shrinkage two weeks post-gel implantation in a triple-negative breast cancer mouse model. Our findings suggest that the RNA-triple-helix hydrogels can be used as an efficient anticancer platform to locally modulate the expression of endogenous miRs in cancer.

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Figure 1: Self-assembled RNA-triple-helix hydrogel nanoconjugates and scaffold for microRNA delivery.
Figure 2: RNA-triple-helix assembly/stability assays and in vitro cellular uptake of RNA–dendrimer nanoparticles into cancer cells.
Figure 3: Cellular trafficking and uptake mechanism of naked dendrimer and RNA-triple-helix–dendrimer conjugates.
Figure 4: Proliferation, migration and survival of cancer cells as a function of RNA-triple-helix nanoparticles treatment.
Figure 5: In vivo miRNA modulation and tumour therapy via RNA-triple-helix hydrogel scaffolds.

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Acknowledgements

J.C. acknowledges a Marie Curie International Outgoing Fellowship and Funding (FP7-PEOPLE-2013-IOF, Project 626386). We thank D. Fulop for helpful and fruitful discussions. We thank the Swanson Biotechnology Center at the Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology (MIT) for assistance with animal experiments and facilities, especially the microscopy, flow cytometry, and histology cores. We also acknowledge that all qPCR experiments done in the KI Genomics Core/MIT BioMicro Center are funded by the NIH and supported in part by the Koch Institute Support Grant P30-CA14051 from the National Cancer Institute and by the National Institute of Environmental Health Sciences of the NIH under award P30-ES002109. We thank D. S. Yun for cryo-TEM assistance at the Peterson Nanotechnology Materials Core Facility. We thank the Department of Comparative Medicine at MIT, especially J. Haupt. We thank G. Paradis for FACS assistance with Cancer Center Support (FACS core) Grant P30-CA14051 from the National Cancer Institute. We thank P. Boisvert and Y. Zhang for technical assistance in SEM at the MIT Center for Materials Science and Engineering (CMSE). These SEM studies made use of the MRSEC Shared Experimental Facilities at MIT, supported by the National Science Foundation under award number DMR-1419807.

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Authors and Affiliations

  1. Harvard-MIT Division for Health Sciences and Technology, Massachusetts Institute of Technology, Institute for Medical Engineering and Science, Cambridge, Massachusetts 02139, USA

    João Conde, Nuria Oliva, Mariana Atilano, Hyun Seok Song & Natalie Artzi

  2. School of Engineering and Materials Science, Queen Mary University of London, London E1 4NS, UK

    João Conde

  3. Grup d’Enginyeria de Materials, Institut Químic de Sarrià-Universitat Ramon Llull, Barcelona 08017, Spain

    Mariana Atilano

  4. Division of Bioconvergence Analysis, Korea Basic Science Institute, Yuseong, Daejeon 169-148, Republic of Korea

    Hyun Seok Song

  5. Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA

    Natalie Artzi

  6. Department of Medicine, Biomedical Engineering Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA

    Natalie Artzi

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  1. João Conde
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Contributions

J.C. and N.A. conceived the project and designed the experiments. J.C., N.O., H.S.S. and M.A. performed the experiments, collected and analysed the data. J.C. and N.A. co-wrote the manuscript. All authors discussed the results and reviewed the manuscript.

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Correspondence to João Conde or Natalie Artzi.

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Conde, J., Oliva, N., Atilano, M. et al. Self-assembled RNA-triple-helix hydrogel scaffold for microRNA modulation in the tumour microenvironment. Nature Mater 15, 353–363 (2016). https://doi.org/10.1038/nmat4497

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