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DNA origami nanostructures can exhibit preferential renal uptake and alleviate acute kidney injury

Abstract

Patients with acute kidney injury (AKI) frequently require kidney transplantation and supportive therapies, such as rehydration and dialysis. Here, we show that radiolabelled DNA origami nanostructures (DONs) with rectangular, triangular and tubular shapes accumulate preferentially in the kidneys of healthy mice and mice with rhabdomyolysis-induced AKI, and that rectangular DONs have renal-protective properties, with efficacy similar to the antioxidant N-acetylcysteine—a clinically used drug that ameliorates contrast-induced AKI and protects kidney function from nephrotoxic agents. We evaluated the biodistribution of DONs non-invasively via positron emission tomography, and the efficacy of rectangular DONs in the treatment of AKI via dynamic positron emission tomography imaging with 68Ga-EDTA, blood tests and kidney tissue staining. DNA-based nanostructures could become a source of therapeutic agents for the treatment of AKI and other renal diseases.

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Fig. 1: Preferential renal accumulation of DONs enabled protection against AKI.
Fig. 2: Biodistribution of DONs in healthy mice.
Fig. 3: Animal study design and PET imaging of 64Cu-Rec-DON in the murine model of AKI.
Fig. 4: ROS scavenging effect of DONs in vitro.
Fig. 5: Dynamic PET imaging using 68Ga-EDTA for evaluation of kidney function.
Fig. 6: Bodyweight change, and blood and kidney tissue analysis after treatment for AKI.

Data availability

The authors declare that all data supporting the findings of this study are available within the paper and its Supplementary Information.

References

  1. 1.

    Bellomo, R., Kellum, J. A. & Ronco, C. Acute kidney injury. Lancet 380, 756–766 (2012).

    Article  Google Scholar 

  2. 2.

    Chawla, L. S., Eggers, P. W., Star, R. A. & Kimmel, P. L. Acute kidney injury and chronic kidney disease as interconnected syndromes. N. Engl. J. Med. 371, 58–66 (2014).

    Article  Google Scholar 

  3. 3.

    Lewington, A. J. P., Cerda, J. & Mehta, R. L. Raising awareness of acute kidney injury: a global perspective of a silent killer. Kidney Int. 84, 457–467 (2013).

    Article  Google Scholar 

  4. 4.

    VA/NIH Acute Renal Failure Trial Network Intensity of renal support in critically ill patients with acute kidney injury. N. Engl. J. Med. 359, 7–20 (2008).

  5. 5.

    Tepel, M. et al. Prevention of radiographic-contrast-agent–induced reductions in renal function by acetylcysteine. N. Engl. J. Med. 343, 180–184 (2000).

    CAS  Article  Google Scholar 

  6. 6.

    Fishbane, S. N-acetylcysteine in the prevention of contrast-induced nephropathy. Clin. J. Am. Soc. Nephrol. 3, 281–287 (2008).

    CAS  Article  Google Scholar 

  7. 7.

    Wagner, V., Dullaart, A., Bock, A.-K. & Zweck, A. The emerging nanomedicine landscape. Nat. Biotechnol. 24, 1211–1217 (2006).

    CAS  Article  Google Scholar 

  8. 8.

    Peer, D. et al. Nanocarriers as an emerging platform for cancer therapy. Nat. Nanotech. 2, 751–760 (2007).

    CAS  Article  Google Scholar 

  9. 9.

    Sun, W. J. et al. Cocoon-like self-degradable DNA nanoclew for anticancer drug delivery. J. Am. Chem. Soc. 136, 14722–14725 (2014).

    CAS  Article  Google Scholar 

  10. 10.

    Min, Y., Caster, J. M., Eblan, M. J. & Wang, A. Z. Clinical translation of nanomedicine. Chem. Rev. 115, 11147–11190 (2015).

    CAS  Article  Google Scholar 

  11. 11.

    Arai, S. et al. Apoptosis inhibitor of macrophage protein enhances intraluminal debris clearance and ameliorates acute kidney injury in mice. Nat. Med. 22, 183–193 (2016).

    CAS  Article  Google Scholar 

  12. 12.

    Kamaly, N., He, J. C., Ausiello, D. A. & Farokhzad, O. C. Nanomedicines for renal disease: current status and future applications. Nat. Rev. Nephrol. 12, 738–753 (2016).

    CAS  Article  Google Scholar 

  13. 13.

    Pelaz, B. et al. Diverse applications of nanomedicine. ACS Nano 11, 2313–2381 (2017).

    CAS  Article  Google Scholar 

  14. 14.

    Alidori, S. et al. Targeted fibrillar nanocarbon RNAi treatment of acute kidney injury. Sci. Transl. Med. 8, 331ra339 (2016).

    Article  Google Scholar 

  15. 15.

    Sun, C. J. et al. Controlling assembly of paired gold clusters within apoferritin nanoreactor for in vivo kidney targeting and biomedical imaging. J. Am. Chem. Soc. 133, 8617–8624 (2011).

    CAS  Article  Google Scholar 

  16. 16.

    Choi, C. H. J., Zuckerman, J. E., Webster, P. & Davis, M. E. Targeting kidney mesangium by nanoparticles of defined size. Proc. Natl Acad. Sci. USA 108, 6656–6661 (2011).

    CAS  Article  Google Scholar 

  17. 17.

    Manne, N. et al. Cerium oxide nanoparticles attenuate acute kidney injury induced by intra-abdominal infection in Sprague-Dawley rats. J. Nanobiotechnol. 13, 75 (2015).

    Article  Google Scholar 

  18. 18.

    Zhang, H. et al. Eupafolin nanoparticle improves acute renal injury induced by LPS through inhibiting ROS and inflammation. Biomed. Pharmacother. 85, 704–711 (2017).

    CAS  Article  Google Scholar 

  19. 19.

    Pinheiro, A. V., Han, D., Shih, W. M. & Yan, H. Challenges and opportunities for structural DNA nanotechnology. Nat. Nanotech. 6, 763–772 (2011).

    CAS  Article  Google Scholar 

  20. 20.

    Seeman, N. C. Nanomaterials based on DNA. Annu. Rev. Biochem. 79, 65–87 (2010).

    CAS  Article  Google Scholar 

  21. 21.

    Zhang, F. et al. Complex wireframe DNA origami nanostructures with multi-arm junction vertices. Nat. Nanotech. 10, 779–784 (2015).

    CAS  Article  Google Scholar 

  22. 22.

    Li, J. et al. Self-assembled multivalent DNA nanostructures for noninvasive intracellular delivery of immunostimulatory CpG oligonucleotides. ACS Nano 5, 8783–8789 (2011).

    CAS  Article  Google Scholar 

  23. 23.

    Mei, Q. et al. Stability of DNA origami nanoarrays in cell lysate. Nano Lett. 11, 1477–1482 (2011).

    CAS  Article  Google Scholar 

  24. 24.

    Hahn, J., Wickham, S. F., Shih, W. M. & Perrault, S. D. Addressing the instability of DNA nanostructures in tissue culture. ACS Nano 8, 8765–8775 (2014).

    CAS  Article  Google Scholar 

  25. 25.

    Surana, S., Shenoy, A. R. & Krishnan, Y. Designing DNA nanodevices for compatibility with the immune system of higher organisms. Nat. Nanotech. 10, 741–747 (2015).

    CAS  Article  Google Scholar 

  26. 26.

    Lee, H. et al. Molecularly self-assembled nucleic acid nanoparticles for targeted in vivo siRNA delivery. Nat. Nanotech. 7, 389–393 (2012).

    CAS  Article  Google Scholar 

  27. 27.

    Zhu, G. et al. Self-assembled, aptamer-tethered DNA nanotrains for targeted transport of molecular drugs in cancer theranostics. Proc. Natl Acad. Sci. USA 110, 7998–8003 (2013).

    CAS  Article  Google Scholar 

  28. 28.

    Torring, T., Helmig, S., Ogilby, P. R. & Gothelf, K. V. Singlet oxygen in DNA nanotechnology. Acc. Chem. Res. 47, 1799–1806 (2014).

    Article  Google Scholar 

  29. 29.

    Chen, Y.-J., Groves, B., Muscat, R. A. & Seelig, G. DNA nanotechnology from the test tube to the cell. Nat. Nanotech. 10, 748–760 (2015).

    CAS  Article  Google Scholar 

  30. 30.

    Chao, J. et al. Hetero-assembly of gold nanoparticles on a DNA origami template. Sci. China Chem. 59, 730–734 (2016).

    CAS  Article  Google Scholar 

  31. 31.

    Du, Y. et al. DNA-nanostructure–gold-nanorod hybrids for enhanced in vivo optoacoustic imaging and photothermal therapy. Adv. Mater. 28, 10000–10007 (2016).

    CAS  Article  Google Scholar 

  32. 32.

    Li, J., Green, A. A., Yan, H. & Fan, C. H. Engineering nucleic acid structures for programmable molecular circuitry and intracellular biocomputation. Nat. Chem. 9, 1056–1067 (2017).

    CAS  Article  Google Scholar 

  33. 33.

    Hu, Q., Li, H., Wang, L., Gu, H. & Fan, C. DNA nanotechnology-enabled drug delivery systems. Chem. Rev. https://doi.org/10.1021/acs.chemrev.7b00663 (2018).

  34. 34.

    Li, S. et al. A DNA nanorobot functions as a cancer therapeutic in response to a molecular trigger in vivo. Nat. Biotechnol. 36, 258–264 (2018).

    CAS  Article  Google Scholar 

  35. 35.

    Zhang, Q. et al. DNA origami as an in vivo drug delivery vehicle for cancer therapy. ACS Nano 8, 6633–6643 (2014).

    CAS  Article  Google Scholar 

  36. 36.

    Jiang, D., England, C. G. & Cai, W. DNA nanomaterials for preclinical imaging and drug delivery. J. Control. Release 239, 27–38 (2016).

    CAS  Article  Google Scholar 

  37. 37.

    Rothemund, P. W. K. Folding DNA to create nanoscale shapes and patterns. Nature 440, 297–302 (2006).

    CAS  Article  Google Scholar 

  38. 38.

    Fu, J., Liu, M., Liu, Y., Woodbury, N. W. & Yan, H. Interenzyme substrate diffusion for an enzyme cascade organized on spatially addressable DNA nanostructures. J. Am. Chem. Soc. 134, 5516–5519 (2012).

    CAS  Article  Google Scholar 

  39. 39.

    Makarova, K. S., Wolf, Y. I. & Koonin, E. V. Comparative genomics of defense systems in archaea and bacteria. Nucleic Acids Res. 41, 4360–4377 (2013).

    CAS  Article  Google Scholar 

  40. 40.

    Lin, M. et al. Programmable engineering of a biosensing interface with tetrahedral DNA nanostructures for ultrasensitive DNA detection. Angew. Chem. Int. Ed. Engl. 54, 2151–2155 (2015).

    CAS  Article  Google Scholar 

  41. 41.

    Jiang, D. et al. Multiple-armed tetrahedral DNA nanostructures for tumor-targeting, dual-modality in vivo imaging. ACS Appl. Mater. Interfaces 8, 4378–4384 (2016).

    CAS  Article  Google Scholar 

  42. 42.

    Keum, J.-W. & Bermudez, H. Enhanced resistance of DNA nanostructures to enzymatic digestion. Chem. Commun. 0, 7036–7038 (2009).

    CAS  Article  Google Scholar 

  43. 43.

    Yamamoto, Y., Nagasaki, Y., Kato, Y., Sugiyama, Y. & Kataoka, K. Long-circulating poly(ethylene glycol)-poly(d,l-lactide) block copolymer micelles with modulated surface charge. J. Control. Release 77, 27–38 (2001).

    CAS  Article  Google Scholar 

  44. 44.

    Alexis, F., Pridgen, E., Molnar, L. K. & Farokhzad, O. C. Factors affecting the clearance and biodistribution of polymeric nanoparticles. Mol. Pharm. 5, 505–515 (2008).

    CAS  Article  Google Scholar 

  45. 45.

    Blanco, E., Shen, H. & Ferrari, M. Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat. Biotechnol. 33, 941–951 (2015).

    CAS  Article  Google Scholar 

  46. 46.

    Albanese, A., Tang, P. S. & Chan, W. C. W. The effect of nanoparticle size, shape, and surface chemistry on biological systems. Annu. Rev. Biomed. Eng. 14, 1–16 (2012).

    CAS  Article  Google Scholar 

  47. 47.

    Du, B. J. et al. Glomerular barrier behaves as an atomically precise bandpass filter in a sub-nanometre regime. Nat. Nanotech. 12, 1096–1102 (2017).

    CAS  Article  Google Scholar 

  48. 48.

    Lacerda, L. et al. Dynamic imaging of functionalized multi-walled carbon nanotube systemic circulation and urinary excretion. Adv. Mater. 20, 225-230 (2008).

    Google Scholar 

  49. 49.

    Ruggiero, A. et al. Paradoxical glomerular filtration of carbon nanotubes. Proc. Natl Acad. Sci. USA 107, 12369–12374 (2010).

    CAS  Article  Google Scholar 

  50. 50.

    Key, J. et al. Soft discoidal polymeric nanoconstructs resist macrophage uptake and enhance vascular targeting in tumors. ACS Nano 9, 11628–11641 (2015).

    CAS  Article  Google Scholar 

  51. 51.

    Williams, R. M. et al. Mesoscale nanoparticles selectively target the renal proximal tubule epithelium. Nano Lett. 15, 2358–2364 (2015).

    CAS  Article  Google Scholar 

  52. 52.

    Boutaud, O. et al. Acetaminophen inhibits hemoprotein-catalyzed lipid peroxidation and attenuates rhabdomyolysis-induced renal failure. Proc. Natl Acad. Sci. USA 107, 2699–2704 (2010).

    CAS  Article  Google Scholar 

  53. 53.

    Singh, A. P. et al. Animal models of acute renal failure. Pharmacol. Rep. 64, 31–44 (2012).

    CAS  Article  Google Scholar 

  54. 54.

    Huang, H. et al. A porphyrin–PEG polymer with rapid renal clearance. Biomaterials 76, 25–32 (2016).

    CAS  Article  Google Scholar 

  55. 55.

    Nath, K. A. & Norby, S. M. Reactive oxygen species and acute renal failure. Am. J. Med. 109, 665–678 (2000).

    CAS  Article  Google Scholar 

  56. 56.

    Valko, M. et al. Free radicals and antioxidants in normal physiological functions and human disease. Int. J. Biochem. Cell Biol. 39, 44–84 (2007).

    CAS  Article  Google Scholar 

  57. 57.

    Hemnani, T. & Parihar, M. Reactive oxygen species and oxidative DNA damage. Indian J. Physiol. Pharmacol. 42, 440–452 (1998).

    CAS  PubMed  Google Scholar 

  58. 58.

    Shyu, K. G., Cheng, J. J. & Kuan, P. Acetylcysteine protects against acute renal damage in patients with abnormal renal function undergoing a coronary procedure. J. Am. Coll. Cardiol. 40, 1383–1388 (2002).

    CAS  Article  Google Scholar 

  59. 59.

    Hofman, M. et al. 68Ga-EDTA PET/CT imaging and plasma clearance for glomerular filtration rate quantification: comparison to conventional 51Cr-EDTA. J. Nucl. Med. 56, 405–409 (2015).

    CAS  Article  Google Scholar 

  60. 60.

    Hofman, M. S. & Hicks, R. J. Gallium-68 EDTA PET/CT for renal imaging. Semin. Nucl. Med. 46, 448–461 (2016).

    Article  Google Scholar 

  61. 61.

    Nair, A. B. & Jacob, S. A simple practice guide for dose conversion between animals and human. J. Basic Clin. Pharm. 7, 27–31 (2016).

    Article  Google Scholar 

  62. 62.

    Uchino, S. et al. Acute renal failure in critically ill patients—a multinational, multicenter study. J. Am. Med. Assoc. 294, 813–818 (2005).

    CAS  Article  Google Scholar 

  63. 63.

    Cadet, J. & Wagner, J. R. DNA base damage by reactive oxygen species, oxidizing agents, and UV radiation. Cold Spring Harb. Perspect. Biol. 5, a012559 (2013).

    Article  Google Scholar 

  64. 64.

    Agnihotri, N. & Mishra, P. C. Mechanism of scavenging action of N-acetylcysteine for the OH radical: a quantum computational study. J. Phys. Chem. B 113, 12096–12104 (2009).

    CAS  Article  Google Scholar 

  65. 65.

    Ponnuswamy, N. et al. Oligolysine-based coating protects DNA nanostructures from low-salt denaturation and nuclease degradation. Nat. Commun. 8, 15654 (2017).

    CAS  Article  Google Scholar 

  66. 66.

    Elbaz, J., Yin, P. & Voigt, C. A. Genetic encoding of DNA nanostructures and their self-assembly in living bacteria. Nat. Commun. 7, 11179 (2016).

    CAS  Article  Google Scholar 

  67. 67.

    Praetorius, F. et al. Biotechnological mass production of DNA origami. Nature 552, 84–87 (2017).

    CAS  Article  Google Scholar 

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Acknowledgements

The authors thank J. J. Jeffery and A. M. Weichmann for help with the small-animal imaging studies. The authors are grateful for insightful input from B. Yu, R. Hernandez, S. Goel, L. Kang and E. B. Ehlerding. This work was supported in part by the University of Wisconsin–Madison, National Institutes of Health (1R01GM104960, P30CA014520 and T32CA009206), National Natural Science Foundation of China (31771036, 51703132 and 51573096), Guangdong Province Natural Science Foundation of Major Basic Research and Cultivation Project (2018B030308003), Fok Ying-Tong Education Foundation for Young Teachers in Higher Education Institutions of China (161032) and Basic Research Program of Shenzhen (JCYJ20170412111100742 and JCYJ20160422091238319). C.F. gratefully acknowledges the National Key R&D Program of China (2016YFA0201200), NSFC (21329501 and 21390414) and Chinese Academy of Sciences (QYZDJ-SSW-SLH031). This work is dedicated to the memory of Q. Huang, whose great insights inspired this project.

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Authors

Contributions

W.C., H.Y., P.H. and C.F. conceived the idea and supervised the project. D.J., Z.G. and H.-J.I. conceived and designed the experiments. Z.G. provided the DNA nanostructures and characterization data. D.J. and H.-J.I. performed the radiolabelling, PET imaging studies, animal model establishment and treatment studies, and analysed the data. Z.G., J.H. and L.Z. performed the DON stability experiments. D.J., Z.G., H.-J.I., C.G.E., D.N. and L.Z. performed the cellular studies. C.J.K. and J.W.E. produced Cu-64. Y.Y. and S.Y.C. provided Ga-68. D.J., Z.G., H.-J.I., C.G.E., Y.L., J.S., P.H., C.F., H.Y. and W.C. prepared the manuscript.

Corresponding authors

Correspondence to Peng Huang or Chunhai Fan or Hao Yan or Weibo Cai.

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The authors declare no competing interests.

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Supplementary information

Supplementary Information

Supplementary figures, tables and references.

Reporting Summary

Supplementary Dataset 1

Rectangular-DON sequence and labelling.

Supplementary Dataset 2

Triangular-DON sequence and labelling.

Supplementary Dataset 3

Tubular-DON sequence and labelling.

Supplementary Video 1

PET imaging of Rec-DON in healthy mice.

Supplementary Video 2

PET imaging of Tri-DON in healthy mice.

Supplementary Video 3

PET imaging of Tub-DON in healthy mice.

Supplementary Video 4

PET imaging of Rec-DON in AKI mice.

Supplementary Video 5

Renal function evaluation using 68Ga-EDTA PET imaging.

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Jiang, D., Ge, Z., Im, HJ. et al. DNA origami nanostructures can exhibit preferential renal uptake and alleviate acute kidney injury. Nat Biomed Eng 2, 865–877 (2018). https://doi.org/10.1038/s41551-018-0317-8

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