Assembling defined DNA nanostructures with anticancer drugs: a metformin/DNA complex nanoplatform with a synergistic antitumor effect for KRAS-mutated lung cancer therapy
Source abstract
Abstract
Abstract Herein, a strategy is proposed to simultaneously deliver the small-molecule drug metformin and siRNA with self-assembled DNA nanostructures. The biomedical application of DNA nanostructures is highly promising but still in its infancy. DNA nanostructures as drug delivery vehicles are conventionally synthesized in a magnesium-containing buffer. We propose using an anticancer drug to assemble DNA nanostructures and deliver them with siRNA for synergistic anticancer therapy. The metformin cargo induces DNA self-assembly into well-defined, uniform nanostructures, producing a drug–DNA nanocomplex with multiple functionalities for cancer therapy. Both tile-based and DNA origami structures can be assembled with metformin. The as-prepared metformin/DNA nanocomplex showed high structural and thermal stability and enzymatic resistance in physiological settings. The metformin in the nanocomplex and the KRASG12C siRNA exerted a strong, synergistic antitumor effect against KRAS-mutated non-small cell lung cancer (NSCLC) both in vitro and in vivo by suppressing the RAS/AKT/mTOR and AMPK/AKT/mTOR signaling pathways. The current study suggests that the assembly of complex DNA nanomaterials with carefully chosen small molecules is key to endowing DNA nanostructures with new functionalities and subsequently expanding their applications in multidisciplinary research fields.
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Research context
OpenAlex topics: Advanced biosensing and bioanalysis techniques · RNA Interference and Gene Delivery · MXene and MAX Phase Materials
SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.
References (32)
Show source-provided references
1. Li, S. et al. A DNA nanorobot functions as a cancer therapeutic in response to a molecular trigger. Nat. Biotechnol. 36, 258 (2018).10.1038/nbt.4071 ↗
2. Mou, Q. et al. DNA Trojan horses: self-assembled floxuridine-containing DNA polyhedra for cancer therapy. Chem. Int. Ed. 56, 12528–12532 (2017).10.1002/anie.201706301 ↗
3. Guo, Y. Y. et al. Stressing the role of DNA as a drug carrier: synthesis of DNA-drug conjugates through grafting chemotherapeutics onto phosphorothioate oligonucleotides. Adv. Mater. 31, e1807533 (2019).10.1002/adma.201807533 ↗
4. Zhao, Y. X., Zeng, A. S. X., Benson, E., Nyström, A. M. & Högberg, B. DNA origami delivery system for cancer therapy with tunable release properties. ACS Nano 6, 8684–8691 (2012).10.1021/nn3022662 ↗
5. Lee, H. et al. Molecularly self-assembled nucleic acid nanoparticles for targeted in vivo siRNA delivery. Nat. Nanotechnol. 7, 389–393 (2012).10.1038/nnano.2012.73 ↗
6. Jiang, Q. et al. DNA origami as a carrier for circumvention of drug resistance. J. Am. Chem. Soc. 134, 13396–13403 (2012).10.1021/ja304263n ↗
7. Pei, H. et al. DNA nanostructure-based biomolecular probe carrier platform for electrochemical biosensing. Adv. Mater. 22, 4754–4758 (2010).10.1002/adma.201002767 ↗
8. Tay, C. Y., Yuan, L. & Leong, D. T. Nature-inspired DNA nanosensor for real-time in situ detection of mRNA in living cells. ACS Nano 9, 5609–5617 (2015).10.1021/acsnano.5b01954 ↗
9. Modi, S. et al. A DNA nanomachine that maps spatial and temporal pH changes inside living cells. Nat. Nanotechnol. 4, 325–330 (2009).10.1038/nnano.2009.83 ↗
10. Giovanni, M. et al. Biosensors: electrochemical quantification of escherichia Coli with DNA nanostructure. Adv. Funct. Mater. 25, 3979 (2015).10.1002/adfm.201570171 ↗
11. Jungmann, R. et al. Multiplexed 3D cellular super-resolution imaging with DNA-PAINT and exchange-PAINT. Nat. Methods 11, 313–318 (2014).10.1038/nmeth.2835 ↗
12. 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).10.1038/ncomms1337 ↗
13. Hu, Q., Li, H., Wang, L., Gu, H. & Fan, C. DNA nanotechnology-enabled drug delivery systems. Chem. Rev. 119, 6459–6506 (2019).10.1021/acs.chemrev.7b00663 ↗
14. Jiang, Q. et al. Rationally designed DNA-based nanocarriers. Adv. Drug. Deliv. Rev. 147, 2–21 (2019).10.1016/j.addr.2019.02.003 ↗
15. Nielsen, T. B. et al. Peptide-directed DNA-templated protein labelling for the assembly of a pseudo-igM. Angew. Chem. Int. Ed. Engl. 58, 9068–9072 (2019).10.1002/anie.201903134 ↗
16. Ponnuswamy, N. et al. Oligolysine-based coating protects DNA nanostructures from low-salt denaturation and nuclease degradation. Nat. Commun. 8, 15654 (2017).10.1038/ncomms15654 ↗
17. Auvinen, H. et al. Protein coating of DNA nanostructures for enhanced stability and immunocompatibility. Adv. Healthc. 6, 1700692 (2017).10.1002/adhm.201700692 ↗
18. Chopra, A., Krishnan, S. & Simmel, F. C. Electrotransfection of polyamine folded DNA origami structures. Nano Lett. 16, 6683–6690 (2016).10.1021/acs.nanolett.6b03586 ↗
19. Wang, D. et al. Isothermal self-assembly of spermidine-DNA nanostructure complex as a functional platform for cancer therapy. Acs. Appl. Mater. Interfaces 10, 15504–15516 (2018).10.1021/acsami.8b03464 ↗
20. Zhao, Y. et al. PolyMetformin combines carrier and anticancer activities for in vivo siRNA delivery. Nat. Commun. 7, 11822 (2016).10.1038/ncomms11822 ↗
21. Zhang, T., Tian T. & Lin, Y. F. Functionalizing framework nucleic-acid-based nanostructures for biomedical application. Adv. Mater. e2107820 (2021).10.1002/adma.202107820 ↗
22. Tian, T. et al. A Framework nucleic acid based robotic nanobee for active targeting therapy. Adv. Funct. Mater. 31, 2007342 (2020).10.1002/adfm.202007342 ↗
23. Ma, W. et al. An intelligent DNA nanorobot with in vitro enhanced protein lysosomal degradation of HER2. Nano Lett. 19, 4505–4517 (2019).10.1021/acs.nanolett.9b01320 ↗
24. Qian, H. et al. Self-assembly of DNA nanotubes with defined diameters and lengths. Small 10, 855–858 (2014).10.1002/smll.201301891 ↗
25. You, Z. et al. Regulation of vascular smooth muscle cell autophagy by DNA nanotube-conjugated mTOR siRNA. Biomaterials 67, 137–150 (2015).10.1016/j.biomaterials.2015.07.015 ↗
26. Han, G., Gong, H., Wang, Y., Guo, S. & Liu, K. AMPK/mTOR-mediated inhibition of survivin partly contributes to metformin-induced apoptosis in human gastric cancer cell. Cancer Biol. 16, 77–87 (2015).10.4161/15384047.2014.987021 ↗
27. Jänne, P. A. et al. Selumetinib plus docetaxel compared with docetaxel alone and progression-free survival in patients with KRAS-mutant advanced non-small cell lung cancer: the SELECT-1 randomized clinical trial. JAMA 317, 1844–1853 (2017).10.1001/jama.2017.3438 ↗
28. Blumenschein, G. R. J. et al. A randomized phase II study of the MEK1/MEK2 inhibitor trametinib (GSK1120212) compared with docetaxel in KRAS-mutant advanced non-small-cell lung cancer (NSCLC). Ann. Oncol. 26, 894–901 (2015).10.1093/annonc/mdv072 ↗
29. Wang, J., Yao, X. & Huang, J. New tricks for human farnesyltransferase inhibitor: cancer and beyond. Medchemcomm 8, 841–854 (2017).10.1039/C7MD00030H ↗
30. Ambrogio, C. et al. KRAS dimerization impacts MEK inhibitor sensitivity and oncogenic activity of mutant KRAS. Cell 172, 857–868 (2018).10.1016/j.cell.2017.12.020 ↗
31. Singh, A., Sowjanya, A. P. & Ramakrishna, G. The wild-type Ras: road ahead. FASEB J. 19, 161–169 (2005).10.1096/fj.04-2584hyp ↗
32. Ma, Y. et al. K-ras gene mutation as a predictor of cancer cell responsiveness to metformin. Mol. Med. Rep. 8, 763–768 (2013).10.3892/mmr.2013.1596 ↗