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Water-soluble Cu30 nanoclusters as a click chemistry catalyst for living cell labeling via azide-alkyne cycloaddition

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Abstract

Cu(I)-catalyzed azide-alkyne cycloadditions (CuAAC) have gained increasing interest in the selective labeling of living cells and organisms with biomolecules. However, their application is constrained either by the high cytotoxicity of Cu(I) ions or the low activity of CuAAC in the internal space of living cells. This paper reports the design of a novel Cu-based nanocatalyst, water-soluble thiolated Cu30 nanoclusters (NCs), for living cell labeling via CuAAC. The Cu30 NCs offer good biocompatibility, excellent stability, and scalable synthesis (e.g., gram scale), which would facilitate potential commercial applications. By combining the highly localized Cu(I) active species on the NC surface and good structural stability, the Cu30 NCs exhibit superior catalytic activities for a series of Huisgen cycloaddition reactions with good recyclability. More importantly, the biocompatibility of the Cu30 NCs enables them to be a good catalyst for CuAAC, whereby the challenging labeling of living cells can be achieved via CuAAC on the cell membrane. This study sheds light on the facile synthesis of atomically precise Cu NCs, as well as the design of novel Cu NCs-based nanocatalysts for CuAAC in intracellular bioorthogonal applications.

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References

  1. Kang, S. W.; Lee, S.; Na, J. H.; Yoon, H. I.; Lee, D. E.; Koo, H.; Cho, Y. W.; Kim, S. H.; Jeong, S. Y.; Kwon, I. C. et al. Cell labeling and tracking method without distorted signals by phagocytosis of macrophages. Theranostics 2014, 4, 420–431.

    Article  Google Scholar 

  2. Chandrasekaran, R.; Madheswaran, T.; Tharmalingam, N.; Bose, R. J. C.; Park, H.; Ha, D. H. Labeling and tracking cells with gold nanoparticles. Drug Discov. Today 2021, 26, 94–105.

    Article  CAS  Google Scholar 

  3. Wang, H.; Mooney, D. J. Metabolic glycan labelling for cancer-targeted therapy. Nat. Chem. 2020, 12, 1102–1114.

    Article  CAS  Google Scholar 

  4. Li, Z. H.; Shen, D. L.; Hu, S. Q.; Su, T.; Huang, K.; Liu, F. R.; Hou, L.; Cheng, K. Pretargeting and bioorthogonal click chemistry-mediated endogenous stem cell homing for heart repair. ACS Nano 2018, 12, 12193–12200.

    Article  CAS  Google Scholar 

  5. Meldal, M.; Diness, F. Recent fascinating aspects of the CuAAC click reaction. Trends Chem. 2020, 2, 569–584.

    Article  CAS  Google Scholar 

  6. Hu, G. S.; Chen, J. J.; Fan, Y.; Zhou, H. Y.; Guo, K. Z.; Fang, Z.; Xie, L. X.; Wang, L.; Wang, Y. J. A promoted copper-catalysed azide-alkyne cycloaddition (CuAAC) for broad spectrum peptide-engineered implants. Chem. Eng. J. 2022, 427, 130918.

    Article  CAS  Google Scholar 

  7. Zhang, R. X.; Chen, Y.; Ding, M. H.; Zhao, J. Heterogeneous Cu catalyst in organic transformations. Nano Res. 2022, 15, 2810–2833.

    Article  Google Scholar 

  8. Kumar, R. A.; Pattanayak, M. R.; Yen-Pon, E.; Eliyan, J.; Porte, K.; Bernard, S.; Riomet, M.; Thuéry, P.; Audisio, D.; Taran, F. Strain-promoted 1, 3-dithiolium-4-olates-alkyne cycloaddition. Angew. Chem., Int. Ed. 2019, 131, 14686–14690.

    Article  Google Scholar 

  9. Chen, J. F.; Li, K.; Bonson, S. E.; Zimmerman, S. C. A bioorthogonal small molecule selective polymeric ‘clickase’. J. Am. Chem. Soc. 2020, 142, 13966–13973.

    Article  CAS  Google Scholar 

  10. Gao, Z. G.; Li, Y. J.; Liu, Z. K.; Zhang, Y.; Chen, F. H.; An, P. J.; Lu, W. J.; Hu, J. Z.; You, C. Q.; Xu, J. et al. Small-molecule-selective organosilica nanoreactors for copper-catalyzed azide-alkyne cycloaddition reactions in cellular and living systems. Nano Lett. 2021, 21, 3401–3409.

    Article  CAS  Google Scholar 

  11. You, Y. W.; Cao, F. F.; Zhao, Y. J.; Deng, Q. Q.; Sang, Y. J.; Li, Y.; Dong, K.; Ren, J. S.; Qu, X. G. Near-infrared light dual-promoted heterogeneous copper nanocatalyst for highly efficient bioorthogonal chemistry in vivo. ACS Nano 2020, 14, 4178–4187.

    Article  CAS  Google Scholar 

  12. Jin, R. C.; Zeng, C. J.; Zhou, M.; Chen, Y. X. Atomically precise colloidal metal nanoclusters and nanoparticles: Fundamentals and opportunities. Chem. Rev. 2016, 116, 10346–10413.

    Article  CAS  Google Scholar 

  13. Chakraborty, I.; Pradeep, T. Atomically precise clusters of noble metals: Emerging link between atoms and nanoparticles. Chem. Rev. 2017, 117, 8208–8271.

    Article  CAS  Google Scholar 

  14. Li, Y. W.; Higaki, T.; Du, X. S.; Jin, R. C. Chirality and surface bonding correlation in atomically precise metal nanoclusters. Adv. Mater. 2020, 32, 1905488.

    Article  CAS  Google Scholar 

  15. Malola, S.; Häkkinen, H. Chiral footprint of the ligand layer in the all-alkynyl-protected gold nanocluster Au144(CCPhF)60. Chem. Commun. 2019, 55, 9460–9462.

    Article  CAS  Google Scholar 

  16. Xiao, Y.; Wu, Z. N.; Yao, Q. F.; Xie, J. P. Luminescent metal nanoclusters: Biosensing strategies and bioimaging applications. Aggregate 2021, 2, 114–132.

    Article  Google Scholar 

  17. Lei, Z.; Wan, X. K.; Yuan, S. F.; Guan, Z. J.; Wang, Q. M. Alkynyl approach toward the protection of metal nanoclusters. Acc. Chem. Res. 2018, 51, 2465–2474.

    Article  CAS  Google Scholar 

  18. Han, Z.; Dong, X. Y.; Luo, P.; Li, S.; Wang, Z. Y.; Zang, S. Q.; Mak, T. C. W. Ultrastable atomically precise chiral silver clusters with more than 95% quantum efficiency. Sci. Adv. 2020, 6, eaay0107.

    Article  CAS  Google Scholar 

  19. Gan, Z. B.; Liu, Y. G.; Wang, L.; Jiang, S. Q.; Xia, N.; Yan, Z. P.; Wu, X.; Zhang, J. R.; Gu, W. M.; He, L. Z. et al. Distance makes a difference in crystalline photoluminescence. Nat. Commun. 2020, 11, 5572.

    Article  CAS  Google Scholar 

  20. Kang, X.; Zhu, M. Z. Tailoring the photoluminescence of atomically precise nanoclusters. Chem. Soc. Rev. 2019, 48, 2422–2457.

    Article  CAS  Google Scholar 

  21. Su, Y.; Xue, T. T.; Liu, Y. X.; Qi, J. X.; Jin, R. C.; Lin, Z. K. Luminescent metal nanoclusters for biomedical applications. Nano Res. 2019, 12, 1251–1265.

    Article  CAS  Google Scholar 

  22. Cai, X.; Hu, W. G.; Xu, S.; Yang, D.; Chen, M. Y.; Shu, M.; Si, R.; Ding, W. P.; Zhu, Y. Structural relaxation enabled by internal vacancy available in a 24-atom gold cluster reinforces catalytic reactivity. J. Am. Chem. Soc. 2020, 142, 4141–4153.

    Article  CAS  Google Scholar 

  23. Qin, L. B.; Sun, F.; Ma, X. S.; Ma, G. Y.; Tang, Y.; Wang, L. K.; Tang, Q.; Jin, R. C.; Tang, Z. H. Homoleptic alkynyl-protected Ag15 nanocluster with atomic precision: Structural analysis and electrocatalytic performance toward CO2 reduction. Angew. Chem., Int. Ed. 2021, 133, 26340–26345.

    Article  Google Scholar 

  24. Narouz, M. R.; Osten, K. M.; Unsworth, P. J.; Man, R. W. Y.; Salorinne, K.; Takano, S.; Tomihara, R.; Kaappa, S.; Malola, S.; Dinh, C. T. et al. N-heterocyclic carbene-functionalized magic-number gold nanoclusters. Nat. Chem. 2019, 11, 419–425.

    Article  CAS  Google Scholar 

  25. Seong, H.; Efremov, V.; Park, G.; Kim, H.; Yoo, J. S.; Lee, D. Atomically precise gold nanoclusters as model catalysts for identifying active sites for electroreduction of CO2. Angew. Chem., Int. Ed. 2021, 60, 14563–14570.

    Article  CAS  Google Scholar 

  26. Zhu, H. G.; Yuan, X.; Yao, Q. F.; Xie, J. P. Shining photocatalysis by gold-based nanomaterials. Nano Energy 2021, 88, 106306.

    Article  CAS  Google Scholar 

  27. Yan, J. Z.; Teo, B. K.; Zheng, N. F. Surface chemistry of atomically precise coinage-metal nanoclusters: From structural control to surface reactivity and catalysis. Acc. Chem. Res. 2018, 51, 3084–3093.

    Article  CAS  Google Scholar 

  28. Huang, R. W.; Wei, Y. S.; Dong, X. Y.; Wu, X. H.; Du, C. X.; Zang, S. Q.; Mak, T. C. W. Hypersensitive dual-function luminescence switching of a silver-chalcogenolate cluster-based metal-organic framework. Nat. Chem. 2017, 9, 689–697.

    Article  CAS  Google Scholar 

  29. Shang, L.; Xu, J.; Nienhaus, G. U. Recent advances in synthesizing metal nanocluster-based nanocomposites for application in sensing, imaging and catalysis. Nano Today 2019, 28, 100767.

    Article  Google Scholar 

  30. Chen, S.; Ma, H. D.; Padelford, J. W.; Qinchen, W.; Yu, W.; Wang, S. X.; Zhu, M. Z.; Wang, G. L. Near infrared electrochemiluminescence of rod-shape 25-atom AuAg nanoclusters that is hundreds-fold stronger than that of Ru(bpy)3 standard. J. Am. Chem. Soc. 2019, 141, 9603–9609.

    Article  CAS  Google Scholar 

  31. Wang, Z. G.; Shi, Y. E.; Yang, X.; Xiong, Y.; Li, Y. X.; Chen, B. K.; Lai, W. F.; Rogach, A. L. Water-soluble biocompatible copolymer hypromellose grafted chitosan able to load exogenous agents and copper nanoclusters with aggregation-induced emission. Adv. Funct. Mater. 2018, 28, 1802848.

    Article  Google Scholar 

  32. Pei, F.; Dai, S. Q.; Guo, B. F.; Xie, H.; Zhao, C. W.; Cui, J. Q.; Fang, X. L.; Chen, C. M.; Zheng, N. F. Titanium-oxo cluster reinforced gel polymer electrolyte enabling lithium-sulfur batteries with high gravimetric energy densities. Energy Environ. Sci. 2021, 14, 975–985.

    Article  CAS  Google Scholar 

  33. Song, Y. B.; Li, Y. W.; Zhou, M.; Liu, X.; Li, H.; Wang, H.; Shen, Y. H.; Zhu, M. Z.; Jin, R. C. Ultrabright Au@Cu14 nanoclusters: 71.3% phosphorescence quantum yield in non-degassed solution at room temperature. Sci. Adv. 2021, 7, eabd2091.

    Article  CAS  Google Scholar 

  34. Zhang, H.; Liu, H.; Tian, Z. Q.; Lu, D.; Yu, Y.; Cestellos-Blanco, S.; Sakimoto, K. K.; Yang, P. D. Bacteria photosensitized by intracellular gold nanoclusters for solar fuel production. Nat. Nanotechnol. 2018, 13, 900–905.

    Article  CAS  Google Scholar 

  35. Jiang, X. Y.; Zhou, Q. H.; Du, B. J.; Li, S. Q.; Huang, Y. Y.; Chi, Z. K.; Lee W. M.; Yu, M. X.; Zheng, J. Noninvasive monitoring of hepatic glutathione depletion through fluorescence imaging and blood testing. Sci. Adv. 2021, 7, eabd9847.

    Article  CAS  Google Scholar 

  36. Lin, Z. K.; Goswami, N.; Xue, T. T.; Chai, O. J. H.; Xu, H. J.; Liu, Y.; Su, Y. X.; Xie, J. P. Engineering metal nanoclusters for targeted therapeutics: From targeting strategies to therapeutic applications. Adv. Funct. Mater. 2021, 31, 2105662.

    Article  CAS  Google Scholar 

  37. Liu, H. L.; Hong, G. S.; Luo, Z. T.; Chen, J. C.; Chang, J. L.; Gong, M.; He, H.; Yang, J.; Yuan, X.; Li, L. L. et al. Atomic-precision gold clusters for NIR-II imaging. Adv. Mater. 2019, 31, 1901015.

    Article  CAS  Google Scholar 

  38. Jiang, X. Y.; Du, B. J.; Zheng, J. Glutathione-mediated biotransformation in the liver modulates nanoparticle transport. Nat. Nanotechnol. 2019, 14, 874–882.

    Article  CAS  Google Scholar 

  39. Zheng, K. Y.; Setyawati, M. I.; Leong, D. T.; Xie, J. P. Antimicrobial silver nanomaterials. Coord. Chem. Rev. 2018, 357, 1–17.

    Article  CAS  Google Scholar 

  40. Song, X. R.; Zhu, W.; Ge, X. G.; Li, R. F.; Li, S. H.; Chen, X.; Song, J. B.; Xie, J. P.; Chen, X. Y.; Yang, H. H. A new class of NIR-II gold nanocluster-based protein biolabels for in vivo tumor-targeted imaging. Angew. Chem., Int. Ed. 2021, 60, 1306–1312.

    Article  CAS  Google Scholar 

  41. Fang, Y. P.; Bao, K.; Zhang, P.; Sheng, H. T.; Yun, Y. P.; Hu, S. X.; Astruc, D.; Zhu, M. Z. Insight into the mechanism of the CuAAC reaction by capturing the crucial Au4Cu4-π-alkyne intermediate. J. Am. Chem. Soc. 2021, 143, 1768–1772.

    Article  CAS  Google Scholar 

  42. Li, Y. L.; Wang, J.; Luo, P.; Ma, X. H.; Dong, X. Y.; Wang, Z. Y.; Du, C. X.; Zang, S. Q.; Mak, T. C. W. Cu14 cluster with partial Cu(0) character: Difference in electronic structure from isostructural silver analog. Adv. Sci. 2019, 6, 1900833.

    Article  CAS  Google Scholar 

  43. Han, B. L.; Liu, Z.; Feng, L.; Wang, Z.; Gupta, R. K.; Aikens, C. M.; Tung, C. H.; Sun, D. Polymorphism in atomically precise Cu23 nanocluster incorporating tetrahedral [Cu4]0 kernel. J. Am. Chem. Soc. 2020, 142, 5834–5841.

    Article  CAS  Google Scholar 

  44. Hossain, S.; Niihori, Y.; Nair, L. V.; Kumar, B.; Kurashige, W.; Negishi, Y. Alloy clusters: Precise synthesis and mixing effects. Acc. Chem. Res. 2018, 51, 3114–3124.

    Article  CAS  Google Scholar 

  45. Zhou, T. Y.; Zhu, J. Y.; Gong, L. S.; Nong, L. T.; Liu, J. B. Amphiphilic block copolymer-guided in situ fabrication of stable and highly controlled luminescent copper nanoassemblies. J. Am. Chem. Soc. 2019, 141, 2852–2856.

    Article  CAS  Google Scholar 

  46. Zhang, X. L.; Wang, Z. P.; Qian, S. Y.; Liu, N. W.; Sui, L. N.; Yuan, X. Effect of subtle changes of isomeric ligands on the synthesis of atomically precise water-soluble gold nanoclusters. Nanoscale 2020, 12, 6449–6455.

    Article  CAS  Google Scholar 

  47. Yao, Q. F.; Yuan, X.; Yu, Y.; Yu, Y.; Xie, J. P.; Lee, J. Y. Introducing amphiphilicity to noble metal nanoclusters via phasetransfer driven ion-pairing reaction. J. Am. Chem. Soc. 2015, 137, 2128–2136.

    Article  CAS  Google Scholar 

  48. Cao, Y. T.; Liu, T. Y.; Chen, T. K.; Zhang, B. H.; Jiang, D. E.; Xie, J. P. Revealing the etching process of water-soluble Au25 nanoclusters at the molecular level. Nat. Commun. 2021, 12, 3212.

    Article  CAS  Google Scholar 

  49. Yuan, X.; Zhang, B.; Luo, Z. T.; Yao, Q. F.; Leong, D. T.; Yan, N.; Xie, J. P. Balancing the rate of cluster growth and etching for gram-scale synthesis of thiolate-protected Au25 nanoclusters with atomic precision. Angew. Chem. 2014, 126, 4711–4715.

    Article  Google Scholar 

  50. Yuan, S. F.; Guan, Z. J.; Liu, W. D.; Wang, Q. M. Solvent-triggered reversible interconversion of all-nitrogen-donor-protected silver nanoclusters and their responsive optical properties. Nat. Commun. 2019, 10, 4032.

    Article  Google Scholar 

  51. Huang, R. W.; Yin, J.; Dong, C. W.; Maity, P.; Hedhili, M. N.; Nematulloev, S.; Alamer, B.; Ghosh, A.; Mohammed, O. F.; Bakr, O. M. [Cu23(PhSe)16(Ph3P)8(H)6]·BF4: Atomic-level insights into cuboidal polyhydrido copper nanoclusters and their quasi-simple cubic self-assembly. ACS Mater. Lett. 2021, 3, 90–99.

    Article  CAS  Google Scholar 

  52. Wu, Z. K.; MacDonald, M. A.; Chen, J.; Zhang, P.; Jin, R. C. Kinetic control and thermodynamic selection in the synthesis of atomically precise gold nanoclusters. J. Am. Chem. Soc. 2011, 133, 9670–9673.

    Article  CAS  Google Scholar 

  53. Shi, Y. E.; Ma, J. Z.; Feng, A. R.; Wang, Z. G.; Rogach, A. L. Aggregation-induced emission of copper nanoclusters. Aggregate 2021, 2, e112.

    Google Scholar 

  54. Desireddy, A.; Conn, B. E.; Guo, J. S.; Yoon, B.; Barnett, R. N.; Monahan, B. M.; Kirschbaum, K.; Griffith, W. P.; Whetten, R. L.; Landman, U. et al. Ultrastable silver nanoparticles. Nature 2013, 501, 399–402.

    Article  CAS  Google Scholar 

  55. Wang, S. X.; Song, Y. B.; Jin, S.; Liu, X.; Zhang, J.; Pei, Y.; Meng, X. M.; Chen, M.; Li, P.; Zhu, M. Z. Metal exchange method using Au25 nanoclusters as templates for alloy nanoclusters with atomic precision. J. Am. Chem. Soc. 2015, 137, 4018–4021.

    Article  CAS  Google Scholar 

  56. Zhang, M. M.; Dong, X. Y.; Wang, Z. Y.; Li, H. Y.; Li, S. J.; Zhao, X. L.; Zang, S. Q. AIE triggers the circularly polarized luminescence of atomically precise enantiomeric copper(I) alkynyl clusters. Angew. Chem. 2020, 132, 10138–10144.

    Article  Google Scholar 

  57. Kong, Y. J.; Yan, Z. P.; Li, S.; Su, H. F.; Li, K.; Zheng, Y. X.; Zang, S. Q. Photoresponsive propeller-like chiral AIE copper(I) clusters. Angew. Chem., Int. Ed. 2020, 59, 5336–5340.

    Article  CAS  Google Scholar 

  58. Prasanth, T.; Chakraborti, G.; Mandal, T.; Ravichandiran, V.; Dash, J. Cycloaddition of N-sulfonyl and N-sulfamoyl azides with alkynes in aqueous media for the selective synthesis of 1,2,3-triazoles. Green Chem. 2022, 24, 911–915.

    Article  CAS  Google Scholar 

  59. Chung, R.; Vo, A.; Fokin, V. V.; Hein, J. E. Catalyst activation, chemoselectivity, and reaction rate controlled by the counterion in the Cu(I)-catalyzed cycloaddition between azide and terminal or 1-iodoalkynes. ACS Catal. 2018, 8, 7889–7897.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 22071127), Taishan Scholar Foundation (No. tsqn201812074); the Natural Science Foundation of Shandong Province (No. ZR2019YQ07), and the NanoBio Lab (IMRE, A⋆STAR, Singapore).

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Authors and Affiliations

  1. School of Materials Science and Engineering, Qingdao University of Science and Technology, Qingdao, 266042, China

    Ge Yang, Yali Xie, Yaru Wang, Fanglin Du & Xun Yuan

  2. Key Lab of Biobased Polymer Materials of Shandong Provincial Education Department, School of Polymer Science and Engineering, Qingdao University of Science and Technology, Qingdao, 266042, China

    Ying Tang & Xianfeng Zhou

  3. NanoBio Lab, Institute of Materials Research and Engineering (IMRE), Agency for Science, Technology and Research (A⋆STAR), 31 Biopolis Way, The Nanos, Singapore, 138669, Singapore

    Leng Leng Chng & Jackie Y. Ying

  4. School of Environment and Material Engineering, Yantai University, Yantai, 264005, China

    Fuyi Jiang

  5. NanoBio Lab, A⋆STAR Infectious Diseases Labs, A⋆STAR, 31 Biopolis Way, The Nanos, Singapore, 138669, Singapore

    Jackie Y. Ying

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  1. Ge Yang
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  2. Yali Xie
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Correspondence to Xianfeng Zhou, Jackie Y. Ying or Xun Yuan.

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Yang, G., Xie, Y., Wang, Y. et al. Water-soluble Cu30 nanoclusters as a click chemistry catalyst for living cell labeling via azide-alkyne cycloaddition. Nano Res. 16, 1748–1754 (2023). https://doi.org/10.1007/s12274-022-4821-5

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