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A ribonucleoprotein octamer for targeted siRNA delivery

Nature Biomedical Engineeringvolume 2pages326337 (2018) | Download Citation

Abstract

Hurdles in cell-specific delivery of small interfering RNA (siRNA) in vivo hinder the clinical translation of RNA interference (RNAi). A fundamental problem concerns conflicting requirements for the design of the delivery vehicles: cationic materials facilitate cargo condensation and endosomolysis, yet hinder in vivo targeting and colloidal stability. Here, we describe a self-assembled, compact (~30 nm) and biocompatible ribonucleoprotein-octamer nanoparticle that achieves endosomal destabilization and targeted delivery. The protein octamer consists of a poly(ethylene glycol) scaffold, a sterically masked endosomolytic peptide and a double-stranded RNA-binding domain, providing a discrete number of siRNA loading sites and a high siRNA payload (>30 wt%), and offering flexibility in both siRNA and targeting-ligand selection. We show that a ribonucleoprotein octamer against the polo-like kinase 1 gene and bearing a ligand that binds to prostate-specific membrane antigen leads to efficient gene silencing in prostate tumour cells in vitro and when intravenously injected in mouse models of prostate cancer. The octamer’s versatile nanocarrier design should offer opportunities for the clinical translation of therapies based on intracellularly acting biologics.

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Change history

  • 12 July 2018

    In the version of this Article originally published, in Fig. 3b, middle row, the units ‘nM’ were incorrect and should have been ‘min’. And, in Fig. 4f, in the bottom row, the data in the middle and right panels were mistakenly duplicated from the panels above. These errors have now been corrected.

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Acknowledgements

This work was supported in part by the National Institutes of Health (R01CA140295), the Department of Bioengineering and the Office of Research at the University of Washington. We are also grateful to L. Tonggu and L. Wang for help with TEM measurements and data interpretation, B. Vessella for help with tumour model establishment and J. Sumida at the University of Washington Analytical Biopharmacy Core for help with the surface plasmon resonance measurements.

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Affiliations

  1. Department of Bioengineering, University of Washington, Seattle, WA, USA

    • Wanyi Tai
    • , Junwei Li
    •  & Xiaohu Gao
  2. Department of Urology, University of Washington, Seattle, WA, USA

    • Eva Corey

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Contributions

W.T. and X.G. conceived the idea and designed the project. W.T. and J.L. performed the experiments. W.T., E.C. and X.G. analysed the data and wrote the paper.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Xiaohu Gao.

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https://doi.org/10.1038/s41551-018-0214-1

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