Origami Insects 2 Pdf Free Download

Abstract

Nanoscale robots have potential as intelligent drug delivery systems that respond to molecular triggers^1,2,3,4. Using DNA origami we constructed an autonomous DNA robot programmed to transport payloads and present them specifically in tumors. Our nanorobot is functionalized on the outside with a DNA aptamer that binds nucleolin, a protein specifically expressed on tumor-associated endothelial cells⁵, and the blood coagulation protease thrombin within its inner cavity. The nucleolin-targeting aptamer serves both as a targeting domain and as a molecular trigger for the mechanical opening of the DNA nanorobot. The thrombin inside is thus exposed and activates coagulation at the tumor site. Using tumor-bearing mouse models, we demonstrate that intravenously injected DNA nanorobots deliver thrombin specifically to tumor-associated blood vessels and induce intravascular thrombosis, resulting in tumor necrosis and inhibition of tumor growth. The nanorobot proved safe and immunologically inert in mice and Bama miniature pigs. Our data show that DNA nanorobots represent a promising strategy for precise drug delivery in cancer therapy.

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References

1
Seeman, N.C. DNA in a material world. Nature 421, 427–431 (2003).

Article Google Scholar
2
Modi, S., Nizak, C., Surana, S., Halder, S. & Krishnan, Y. Two DNA nanomachines map pH changes along intersecting endocytic pathways inside the same cell. Nat. Nanotechnol. 8, 459–467 (2013).

CAS Article Google Scholar
3
Douglas, S.M., Bachelet, I. & Church, G.M. A logic-gated nanorobot for targeted transport of molecular payloads. Science 335, 831–834 (2012).

CAS Article Google Scholar
4
Amir, Y. et al. Universal computing by DNA origami robots in a living animal. Nat. Nanotechnol. 9, 353–357 (2014).

CAS Article Google Scholar
5
Huang, Y. et al. The angiogenic function of nucleolin is mediated by vascular endothelial growth factor and nonmuscle myosin. Blood 107, 3564–3571 (2006).

CAS Article Google Scholar
6
Jungmann, R. et al. Multiplexed 3D cellular super-resolution imaging with DNA-PAINT and Exchange-PAINT. Nat. Methods 11, 313–318 (2014).

CAS Article Google Scholar
7
Bhatia, D., Surana, S., Chakraborty, S., Koushika, S.P. & Krishnan, Y. A synthetic icosahedral DNA-based host-cargo complex for functional in vivo imaging. Nat. Commun. 2, 339 (2011).

Article Google Scholar
8
Lee, H. et al. Molecularly self-assembled nucleic acid nanoparticles for targeted in vivo siRNA delivery. Nat. Nanotechnol. 7, 389–393 (2012).

CAS Article Google Scholar
9
Chauhan, V.P. & Jain, R.K. Strategies for advancing cancer nanomedicine. Nat. Mater. 12, 958–962 (2013).

CAS Article Google Scholar
10
Huang, X. et al. Tumor infarction in mice by antibody-directed targeting of tissue factor to tumor vasculature. Science 275, 547–550 (1997).

CAS Article Google Scholar
11
Hu, P. et al. Comparison of three different targeted tissue factor fusion proteins for inducing tumor vessel thrombosis. Cancer Res. 63, 5046–5053 (2003).

CAS PubMed Google Scholar
12
Jain, R.K. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307, 58–62 (2005).

CAS Article Google Scholar
13
Agemy, L. et al. Nanoparticle-induced vascular blockade in human prostate cancer. Blood 116, 2847–2856 (2010).

CAS Article Google Scholar
14
Sambrano, G.R., Weiss, E.J., Zheng, Y.W., Huang, W. & Coughlin, S.R. Role of thrombin signalling in platelets in haemostasis and thrombosis. Nature 413, 74–78 (2001).

CAS Article Google Scholar
15
Pinheiro, A.V., Han, D., Shih, W.M. & Yan, H. Challenges and opportunities for structural DNA nanotechnology. Nat. Nanotechnol. 6, 763–772 (2011).

CAS Article Google Scholar
16
Rothemund, P.W.K. Folding DNA to create nanoscale shapes and patterns. Nature 440, 297–302 (2006).

CAS Article Google Scholar
17
Gerling, T., Wagenbauer, K.F., Neuner, A.M. & Dietz, H. Dynamic DNA devices and assemblies formed by shape-complementary, non-base pairing 3D components. Science 347, 1446–1452 (2015).

CAS Article Google Scholar
18
Benson, E. et al. DNA rendering of polyhedral meshes at the nanoscale. Nature 523, 441–444 (2015).

CAS Article Google Scholar
19
Schüller, V.J. et al. Cellular immunostimulation by CpG-sequence-coated DNA origami structures. ACS Nano 5, 9696–9702 (2011).

Article Google Scholar
20
Jiang, Q. et al. DNA origami as a carrier for circumvention of drug resistance. J. Am. Chem. Soc. 134, 13396–13403 (2012).

CAS Article Google Scholar
21
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
22
Chen, Y.J., Groves, B., Muscat, R.A. & Seelig, G. DNA nanotechnology from the test tube to the cell. Nat. Nanotechnol. 10, 748–760 (2015).

CAS Article Google Scholar
23
Soundararajan, S., Chen, W., Spicer, E.K., Courtenay-Luck, N. & Fernandes, D.J. The nucleolin targeting aptamer AS1411 destabilizes Bcl-2 messenger RNA in human breast cancer cells. Cancer Res. 68, 2358–2365 (2008).

CAS Article Google Scholar
24
Nutiu, R. & Li, Y. Structure-switching signaling aptamers. J. Am. Chem. Soc. 125, 4771–4778 (2003).

CAS Article Google Scholar
25
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
26
Kong, G., Braun, R.D. & Dewhirst, M.W. Hyperthermia enables tumor-specific nanoparticle delivery: effect of particle size. Cancer Res. 60, 4440–4445 (2000).

CAS PubMed Google Scholar
27
Zhang, H. et al. Identification of urine protein biomarkers with the potential for early detection of lung cancer. Sci. Rep. 5, 11805 (2015).

Article Google Scholar
28
Surana, S., Shenoy, A.R. & Krishnan, Y. Designing DNA nanodevices for compatibility with the immune system of higher organisms. Nat. Nanotechnol. 10, 741–747 (2015).

CAS Article Google Scholar
29
Liu, Y., Zeng, B.H., Shang, H.T., Cen, Y.Y. & Wei, H. Bama miniature pigs (Sus scrofa domestica) as a model for drug evaluation for humans: comparison of in vitro metabolism and in vivo pharmacokinetics of lovastatin. Comp. Med. 58, 580–587 (2008).

CAS PubMed PubMed Central Google Scholar
30
Goldberg, S.N. et al. Image-guided tumor ablation: proposal for standardization of terms and reporting criteria. Radiology 228, 335–345 (2003).

Article Google Scholar
31
Miniard, A.C., Middleton, L.M., Budiman, M.E., Gerber, C.A. & Driscoll, D.M. Nucleolin binds to a subset of selenoprotein mRNAs and regulates their expression. Nucleic Acids Res. 38, 4807–4820 (2010).

CAS Article Google Scholar
32
Thompson, J.S. et al. BAFF binds to the tumor necrosis factor receptor-like molecule B cell maturation antigen and is important for maintaining the peripheral B cell population. J. Exp. Med. 192, 129–135 (2000).

CAS Article Google Scholar
33
Douglas, S.M., Chou, J.J. & Shih, W.M. DNA-nanotube-induced alignment of membrane proteins for NMR structure determination. Proc. Natl. Acad. Sci. USA 104, 6644–6648 (2007).

CAS Article Google Scholar
34
Alvarez-Erviti, L. et al. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat. Biotechnol. 29, 341–345 (2011).

CAS Article Google Scholar
35
Guyer, R.A. & Macara, I.G. Loss of the polarity protein PAR3 activates STAT3 signaling via an atypical protein kinase C (aPKC)/NF-κB/interleukin-6 (IL-6) axis in mouse mammary cells. J. Biol. Chem. 290, 8457–8468 (2015).

CAS Article Google Scholar
36
Gottfries, J., Melgar, S. & Michaëlsson, E. Modelling of mouse experimental colitis by global property screens: a holistic approach to assess drug effects in inflammatory bowel disease. PLoS One 7, e30005 (2012).

CAS Article Google Scholar
37
O'Callaghan, P., Li, J.P., Lannfelt, L., Lindahl, U. & Zhang, X. Microglial heparan sulfate proteoglycans facilitate the cluster-of-differentiation 14 (CD14)/Toll-like receptor 4 (TLR4)-dependent inflammatory response. J. Biol. Chem. 290, 14904–14914 (2015).

CAS Article Google Scholar

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Acknowledgements

The authors thank L.Z. Xu (Medical and Health Analysis Center of Peking University) for animal imaging and G. Z. Shi (Laboratory Animal Center of Institute of Biophysics, Chinese Academy of Sciences) for histological examination of minipigs. We also thank A. Sheftel from High Impact Editing for improving the English of the manuscript. This work was supported by grants from National Basic Research Plan of China (MoST Program 2016YFA0201601 to G.N. and B.D.), the National Natural Science Foundation of China (31730032 to G.N., 21222311, 21573051, 91127021 to B.D., the National Distinguished Young Scientists program 31325010 to G.N.), Innovation Research Group of National Natural Science Foundation (11621505 to G.N. and Yuliang Z., 21721002 to B.D.), Beijing Municipal Science & Technology Commission (Z161100000116035 to G.N., Z161100000116036 to B.D.), CAS Interdisciplinary Innovation Team to B.D., G.N. & Yuliang Z., Key Research Program of Frontier Sciences, CAS, Grant No. QYZDB-SSW-SLH029 to B.D. and US National Institute of Health Director's Transformative Research Award (R01GM104960-01 to H.Y.).

Author information

Author notes

Suping Li, Qiao Jiang, Shaoli Liu and Yinlong Zhang: These authors contributed equally to this work.

Affiliations

CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, CAS Key Laboratory of Nanosystem and Hierarchical Fabrication, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, China, Beijing, China.

Suping Li, Qiao Jiang, Shaoli Liu, Yinlong Zhang, Yanhua Tian, Chen Song, Jing Wang, Yiguo Zou, Guangjun Nie, Baoquan Ding & Yuliang Zhao
University of Chinese Academy of Sciences, Beijing, China

Suping Li, Shaoli Liu, Guangjun Nie, Baoquan Ding & Yuliang Zhao
College of Pharmaceutical Science, Jilin University, Changchun, China

Yinlong Zhang
Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China

Yanhua Tian
QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia

Gregory J Anderson
Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China

Jing-Yan Han
School of Molecular Sciences, Center for Molecular Design and Biomimetics

Yung Chang, Yan Liu & Hao Yan
School of Life Sciences, Center for Immunotherapy, Vaccines, and Virotherapy at the Biodesign Institute, Arizona State University, Tempe, Arizona, USA

Yung Chang, Yan Liu & Hao Yan
Institute of Zoology, Chinese Academy of Sciences, Beijing, China

Chen Zhang & Guangbiao Zhou
Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China

Liang Chen

Contributions

Suping L., Q.J., Shaoli L., Yinlong Z., Y.T., C.S., B.D., Yuliang Z. and G.N. conceived and designed the experiments. Suping L., Q.J., Shaoli L., Yinlong Z., C.S., Y.T. and C.Z. performed the experiments. Y.T., C.S., H.Y., B.D., Yinlong Z. and G.N. collected and analyzed the data. J.W., G.A., J.H., Yiguo Z., Y.C., Y.L., L.C., G.-B.Z., G.Z. and C.Z. provided suggestions and technical support on the project. H.Y., B.D., Yuliang Z., and G.N. supervised the project. Suping L., Q.J., H.Y., B.D. and G.N. wrote the manuscript. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Guangjun Nie, Hao Yan, Baoquan Ding or Yuliang Zhao.

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An international provisional patent has been filed based on this work.

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Li, S., Jiang, Q., Liu, 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). https://doi.org/10.1038/nbt.4071

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