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.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
The authors declare that all data supporting the findings of this study are available within the paper and its Supplementary Information.
Bellomo, R., Kellum, J. A. & Ronco, C. Acute kidney injury. Lancet 380, 756–766 (2012).
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).
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).
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).
Tepel, M. et al. Prevention of radiographic-contrast-agent–induced reductions in renal function by acetylcysteine. N. Engl. J. Med. 343, 180–184 (2000).
Fishbane, S. N-acetylcysteine in the prevention of contrast-induced nephropathy. Clin. J. Am. Soc. Nephrol. 3, 281–287 (2008).
Wagner, V., Dullaart, A., Bock, A.-K. & Zweck, A. The emerging nanomedicine landscape. Nat. Biotechnol. 24, 1211–1217 (2006).
Peer, D. et al. Nanocarriers as an emerging platform for cancer therapy. Nat. Nanotech. 2, 751–760 (2007).
Sun, W. J. et al. Cocoon-like self-degradable DNA nanoclew for anticancer drug delivery. J. Am. Chem. Soc. 136, 14722–14725 (2014).
Min, Y., Caster, J. M., Eblan, M. J. & Wang, A. Z. Clinical translation of nanomedicine. Chem. Rev. 115, 11147–11190 (2015).
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).
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).
Pelaz, B. et al. Diverse applications of nanomedicine. ACS Nano 11, 2313–2381 (2017).
Alidori, S. et al. Targeted fibrillar nanocarbon RNAi treatment of acute kidney injury. Sci. Transl. Med. 8, 331ra339 (2016).
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).
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).
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).
Zhang, H. et al. Eupafolin nanoparticle improves acute renal injury induced by LPS through inhibiting ROS and inflammation. Biomed. Pharmacother. 85, 704–711 (2017).
Pinheiro, A. V., Han, D., Shih, W. M. & Yan, H. Challenges and opportunities for structural DNA nanotechnology. Nat. Nanotech. 6, 763–772 (2011).
Seeman, N. C. Nanomaterials based on DNA. Annu. Rev. Biochem. 79, 65–87 (2010).
Zhang, F. et al. Complex wireframe DNA origami nanostructures with multi-arm junction vertices. Nat. Nanotech. 10, 779–784 (2015).
Li, J. et al. Self-assembled multivalent DNA nanostructures for noninvasive intracellular delivery of immunostimulatory CpG oligonucleotides. ACS Nano 5, 8783–8789 (2011).
Mei, Q. et al. Stability of DNA origami nanoarrays in cell lysate. Nano Lett. 11, 1477–1482 (2011).
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).
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).
Lee, H. et al. Molecularly self-assembled nucleic acid nanoparticles for targeted in vivo siRNA delivery. Nat. Nanotech. 7, 389–393 (2012).
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).
Torring, T., Helmig, S., Ogilby, P. R. & Gothelf, K. V. Singlet oxygen in DNA nanotechnology. Acc. Chem. Res. 47, 1799–1806 (2014).
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).
Chao, J. et al. Hetero-assembly of gold nanoparticles on a DNA origami template. Sci. China Chem. 59, 730–734 (2016).
Du, Y. et al. DNA-nanostructure–gold-nanorod hybrids for enhanced in vivo optoacoustic imaging and photothermal therapy. Adv. Mater. 28, 10000–10007 (2016).
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).
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).
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).
Zhang, Q. et al. DNA origami as an in vivo drug delivery vehicle for cancer therapy. ACS Nano 8, 6633–6643 (2014).
Jiang, D., England, C. G. & Cai, W. DNA nanomaterials for preclinical imaging and drug delivery. J. Control. Release 239, 27–38 (2016).
Rothemund, P. W. K. Folding DNA to create nanoscale shapes and patterns. Nature 440, 297–302 (2006).
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).
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).
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).
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).
Keum, J.-W. & Bermudez, H. Enhanced resistance of DNA nanostructures to enzymatic digestion. Chem. Commun. 0, 7036–7038 (2009).
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).
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).
Blanco, E., Shen, H. & Ferrari, M. Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat. Biotechnol. 33, 941–951 (2015).
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).
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).
Lacerda, L. et al. Dynamic imaging of functionalized multi-walled carbon nanotube systemic circulation and urinary excretion. Adv. Mater. 20, 225-230 (2008).
Ruggiero, A. et al. Paradoxical glomerular filtration of carbon nanotubes. Proc. Natl Acad. Sci. USA 107, 12369–12374 (2010).
Key, J. et al. Soft discoidal polymeric nanoconstructs resist macrophage uptake and enhance vascular targeting in tumors. ACS Nano 9, 11628–11641 (2015).
Williams, R. M. et al. Mesoscale nanoparticles selectively target the renal proximal tubule epithelium. Nano Lett. 15, 2358–2364 (2015).
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).
Singh, A. P. et al. Animal models of acute renal failure. Pharmacol. Rep. 64, 31–44 (2012).
Huang, H. et al. A porphyrin–PEG polymer with rapid renal clearance. Biomaterials 76, 25–32 (2016).
Nath, K. A. & Norby, S. M. Reactive oxygen species and acute renal failure. Am. J. Med. 109, 665–678 (2000).
Valko, M. et al. Free radicals and antioxidants in normal physiological functions and human disease. Int. J. Biochem. Cell Biol. 39, 44–84 (2007).
Hemnani, T. & Parihar, M. Reactive oxygen species and oxidative DNA damage. Indian J. Physiol. Pharmacol. 42, 440–452 (1998).
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).
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).
Hofman, M. S. & Hicks, R. J. Gallium-68 EDTA PET/CT for renal imaging. Semin. Nucl. Med. 46, 448–461 (2016).
Nair, A. B. & Jacob, S. A simple practice guide for dose conversion between animals and human. J. Basic Clin. Pharm. 7, 27–31 (2016).
Uchino, S. et al. Acute renal failure in critically ill patients—a multinational, multicenter study. J. Am. Med. Assoc. 294, 813–818 (2005).
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).
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).
Ponnuswamy, N. et al. Oligolysine-based coating protects DNA nanostructures from low-salt denaturation and nuclease degradation. Nat. Commun. 8, 15654 (2017).
Elbaz, J., Yin, P. & Voigt, C. A. Genetic encoding of DNA nanostructures and their self-assembly in living bacteria. Nat. Commun. 7, 11179 (2016).
Praetorius, F. et al. Biotechnological mass production of DNA origami. Nature 552, 84–87 (2017).
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.
The authors declare no competing interests.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary figures, tables and references.
Rectangular-DON sequence and labelling.
Triangular-DON sequence and labelling.
Tubular-DON sequence and labelling.
PET imaging of Rec-DON in healthy mice.
PET imaging of Tri-DON in healthy mice.
PET imaging of Tub-DON in healthy mice.
PET imaging of Rec-DON in AKI mice.
Renal function evaluation using 68Ga-EDTA PET imaging.
About this article
Cite this article
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
Journal of Nanobiotechnology (2021)
Tracking endocytosis and intracellular distribution of spherical nucleic acids with correlative single-cell imaging
Nature Protocols (2021)
Nature Reviews Methods Primers (2021)
Catalytic activity tunable ceria nanoparticles prevent chemotherapy-induced acute kidney injury without interference with chemotherapeutics
Nature Communications (2021)
Nature Communications (2021)