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siRNA-functionalized lanthanide nanoparticle enables efficient endosomal escape and cancer treatment

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Abstract

Attaching DNA/RNA to nanomaterials is the basis for nucleic acid-based assembly and drug delivery. Herein, we report that small interfering RNA (siRNA) effectively coordinates with ligand-free lanthanide nanoparticles (NaGdF4 NPs), and forms siRNA/NaGdF4 spherical nucleic acids (SNA). The coordination is primarily attributed to the interaction between Gd and phosphate backbone of the siRNA. Surprisingly, an efficient encapsulation and rapid endosomal escape of siRNA from the endosome/lysosome were achieved, due to its flexible ability to bound to phospholipid head of endosomal membrane, thereby disrupting the membrane structure. Resorting to the dual properties of NaGdF4 NPs, siRNA loading, and endosomal escape, siRNA targeting programmed cell death-ligand 1 (siPD-L1)/NaGdF4 SNA triggers significant gene silencing in vitro and in vivo, and effectively represses the tumor growth in both CT26 tumor model and 4T1 orthotopic murine model.

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References

  1. Dong, H.; Du, S. R.; Zheng, X. Y.; Lyu, G. M.; Sun, L. D.; Li, L. D.; Zhang, P. Z.; Zhang, C.; Yan, C. H. Lanthanide nanoparticles: From design toward bioimaging and therapy. Chem. Rev. 2015, 115, 10725–10815.

    Article  CAS  Google Scholar 

  2. Gupta, S. K.; Kadam, R. M.; Pujari, P. K. Lanthanide spectroscopy in probing structure—property correlation in multi-site photoluminescent phosphors. Coord. Chem. Rev. 2020, 420, 213405.

    Article  CAS  Google Scholar 

  3. Zhou, W. H.; Saran, R.; Liu, J. W. Metal sensing by DNA. Chem. Rev. 2017, 117, 8272–8325.

    Article  CAS  Google Scholar 

  4. Pu, F.; Ren, J. S.; Qu, X. G. Nucleobases, nucleosides, and nucleotides: Versatile biomolecules for generating functional nanomaterials. Chem. Soc. Rev. 2018, 47, 1285–1306.

    Article  CAS  Google Scholar 

  5. He, Y. P.; Lopez, A.; Zhang, Z. J.; Chen, D.; Yang, R. H.; Liu, J. W. Nucleotide and DNA coordinated lanthanides: From fundamentals to applications. Coord. Chem. Rev. 2019, 387, 235–248.

    Article  CAS  Google Scholar 

  6. Jastrząb, R.; Nowak, M.; Skrobańska, M.; Tolińska, A.; Zabiszak, M.; Gabryel, M.; Marciniak, Ł.; Kaczmarek, M. T. DNA as a target for lanthanide(III) complexes influence. Coord. Chem. Rev. 2019, 382, 145–159.

    Article  Google Scholar 

  7. Ge, H.; Wang, D. Y.; Pan, Y.; Guo, Y. Y.; Li, H. Y.; Zhang, F.; Zhu, X. Y.; Li, Y. H.; Zhang, C.; Huang, L. Sequence-dependent DNA functionalization of upconversion nanoparticles and their programmable assemblies. Angew. Chem., Int. Ed. 2020, 59, 8133–8137.

    Article  CAS  Google Scholar 

  8. Xu, L.; Zhang, P. P.; Liu, Y.; Fang, X. Q.; Zhang, Z. J.; Liu, Y. B.; Peng, L. L.; Liu, J. W. Continuously tunable nucleotide/lanthanide coordination nanoparticles for DNA adsorption and sensing. ACS Omega 2018, 3, 9043–9051.

    Article  CAS  Google Scholar 

  9. Lu, C.; Huang, Z. C.; Liu, B. W.; Liu, Y. B.; Ying, Y. B.; Liu, J. W. Poly-cytosine DNA as a high-affinity ligand for inorganic nanomaterials. Angew. Chem., Int. Ed. 2017, 56, 6208–6212.

    Article  CAS  Google Scholar 

  10. Lopez, A.; Zhao, Y.; Huang, Z. C.; Guo, Y. F.; Guan, S. K.; Jia, Y.; Liu, J. W. Poly-cytosine deoxyribonucleic acid strongly anchoring on graphene oxide due to flexible backbone phosphate interactions. Adv. Mater. Interfaces 2021, 8, 2001798.

    Article  CAS  Google Scholar 

  11. Wittrup, A.; Lieberman, J. Knocking down disease: A progress report on siRNA therapeutics. Nat. Rev. Genet. 2015, 16, 543–552.

    Article  CAS  Google Scholar 

  12. Yonezawa, S.; Koide, H.; Asai, T. Recent advances in siRNA delivery mediated by lipid-based nanoparticles. Adv. Drug Deliv. Rev. 2020, 154-155, 64–78.

    Article  Google Scholar 

  13. Whitehead, K. A.; Langer, R.; Anderson, D. G. Knocking down barriers: Advances in siRNA delivery. Nat. Rev. Drug Discov. 2009, 8, 129–138.

    Article  CAS  Google Scholar 

  14. Liu, J.; Chen, C.; Wei, T.; Gayet, O.; Loncle, C.; Borge, L.; Dusetti, N.; Ma, X. W.; Marson, D.; Laurini, E. et al. Dendrimeric nanosystem consistently circumvents heterogeneous drug response and resistance in pancreatic cancer. Exploration 2021, 1, 21–34.

    Article  Google Scholar 

  15. Wang, Z. R.; Song, L. L.; Liu, Q.; Tian, R.; Shang, Y. X.; Liu, F. S.; Liu, S. L.; Zhao, S.; Han, Z. H.; Sun, J. S. et al. A tubular DNA nanodevice as a siRNA/chemo-drug co-delivery vehicle for combined cancer therapy. Angew. Chem., Int. Ed. 2021, 60, 2594–2598.

    Article  CAS  Google Scholar 

  16. Rahman, M. A.; Wang, P. F.; Zhao, Z. X.; Wang, D. S.; Nannapaneni, S.; Zhang, C.; Chen, Z. J.; Griffith, C. C.; Hurwitz, S. J.; Chen, Z. G. et al. Systemic delivery of Bc12-targeting siRNA by DNA nanoparticles suppresses cancer cell growth. Angew. Chem., Int. Ed. 2017, 56, 16023–16027.

    Article  CAS  Google Scholar 

  17. Liu, J. B.; Lu, X. H.; Wu, T. T.; Wu, X. H.; Han, L.; Ding, B. Q. Branched antisense and siRNA co-assembled nanoplatform for combined gene silencing and tumor therapy. Angew. Chem., Int. Ed. 2021, 60, 1853–1860.

    Article  CAS  Google Scholar 

  18. Guo, S.; Li, K.; Hu, B.; Li, C. H.; Zhang, M. J.; Hussain, A.; Wang, X. X.; Cheng, Q.; Yang, F.; Ge, K. et al. Membrane-destabilizing ionizable lipid empowered imaging-guided siRNA delivery and cancer treatment. Exploration 2021, 1, 35–49.

    Article  Google Scholar 

  19. Costa, D.; Burrows, H. D.; Da Graça Miguel, M. Changes in hydration of lanthanide ions on binding to DNA in aqueous solution. Langmuir 2005, 21, 10492–10496.

    Article  CAS  Google Scholar 

  20. Wang, G. J.; Angelovski, G. Highly potent MRI contrast agent displaying outstanding sensitivity to zinc ions. Angew. Chem., Int. Ed. 2021, 60, 5734–5738.

    Article  CAS  Google Scholar 

  21. Zhao, M. Y.; Wang, R.; Li, B. H.; Fan, Y.; Wu, Y. F.; Zhu, X. Y.; Zhang, F. Precise in vivo inflammation imaging using in situ responsive cross-linking of glutathione-modified ultra-small NIR-II lanthanide nanoparticles. Angew. Chem., Int. Ed. 2019, 58, 2050–2054.

    Article  CAS  Google Scholar 

  22. Liu, Y. B.; Liu, J. W. Growing a nucleotide/lanthanide coordination polymer shell on liposomes. Langmuir 2019, 35, 11217–11224.

    Article  CAS  Google Scholar 

  23. Liu, Y. B.; Liu, J. W. Leakage and rupture of lipid membranes by charged polymers and nanoparticles. Langmuir 2020, 36, 810–818.

    Article  Google Scholar 

  24. Sabin, J.; Prieto, G.; Sennato, S.; Ruso, J. M.; Angelini, R.; Bordi, F.; Sarmiento, F. Effect of Gd3+ on the colloidal stability of liposomes. Phys. Rev. E 2006, 74, 031913.

    Article  Google Scholar 

  25. Azuma, Y.; Imai, H.; Kawaguchi, Y.; Nakase, I.; Kimura, H.; Futaki, S. Modular redesign of a cationic lytic peptide to promote the endosomal escape of biomacromolecules. Angew. Chem., Int. Ed. 2018, 57, 12771–12774.

    Article  CAS  Google Scholar 

  26. Signarvic, R. S.; DeGrado, W. F. Metal-binding dependent disruption of membranes by designed helices. J. Am. Chem. Soc. 2009, 131, 3377–3384.

    Article  CAS  Google Scholar 

  27. Erazo-Oliveras, A.; Najjar, K.; Truong, D.; Wang, T. Y.; Brock, D. J.; Prater, A. R.; Pellois, J. P. The late endosome and its lipid BMP act as gateways for efficient cytosolic access of the delivery agent dfTAT and its macromolecular cargos. Cell Chem. Biol. 2016, 23, 598–607.

    Article  CAS  Google Scholar 

  28. Van Meer, G.; Voelker, D. R.; Feigenson, G. W. Membrane lipids: Where they are and how they behave. Nat. Rev. Mol. Cell Biol. 2008, 9, 112–124.

    Article  CAS  Google Scholar 

  29. Liu, C. Y.; Gao, Z. Y.; Zeng, J. F.; Hou, Y.; Fang, F.; Li, Y. L.; Qiao, R. R.; Shen, L.; Lei, H.; Yang, W. S. et al. Magnetic/upconversion fluorescent NaGdF4: Yb, Er nanoparticle-based dual-modal molecular probes for imaging tiny tumors in vivo. ACS Nano 2013, 7, 7227–7240.

    Article  CAS  Google Scholar 

  30. Bogdan, N.; Vetrone, F.; Ozin, G. A.; Capobianco, J. A. Synthesis of ligand-free colloidally stable water dispersible brightly luminescent lanthanide-doped upconverting nanoparticles. Nano Lett. 2011, 11, 835–840.

    Article  CAS  Google Scholar 

  31. Collier, J. L.; Weiss, S. A.; Pauken, K. E.; Sen, D. R.; Sharpe, A. H. Not-so-opposite ends of the spectrum: CD8+ T cell dysfunction across chronic infection, cancer and autoimmunity. Nat. Immunol. 2021, 22, 809–819.

    Article  CAS  Google Scholar 

  32. Li, C. H.; Zhou, J. H.; Wu, Y. D.; Dong, Y. L.; Du, L. L.; Yang, T. R.; Wang, Y. H.; Guo, S.; Zhang, M. J.; Hussain, A. et al. Core role of hydrophobic core of polymeric nanomicelle in endosomal escape of siRNA. Nano Lett. 2021, 21, 3680–3689.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was financially supported by the Beijing Nova Program from Beijing Municipal Science & Technology Commission (No. Z201100006820005), the Beijing-Tianjin-Hebei Basic Research Cooperation Project (No. 19JCZDJC64100), the National Key Research & Development Program of China (Nos. 2018YFE0117800, 2021YFA1201000, and 2021YFE0106900), the National Natural Science Foundation of China (Nos. 32030060 and 31871003), and the Natural Science Foundation of China international collaboration key project (No. 51861135103). We thank Biological & Medical Engineering Core Facilities (Beijing Institute of Technology) for providing advanced equipment.

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Author notes

  1. Chanchan Yu and Kun Li contributed equally to this work.

Authors and Affiliations

  1. School of Life Science, Advanced Research Institute of Multidisciplinary Science, School of Medical Technology (Institute of Engineering Medicine), Key Laboratory of Molecular Medicine and Biotherapy, Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, Beijing Institute of Technology, Beijing, 100081, China

    Chanchan Yu, Kun Li, Lin Xu, Bo Li, Chunhui Li, Shuai Guo, Ziyue Li, Yuquan Zhang, Abid Hussain & Yuanyu Huang

  2. CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing, 100190, China

    Chanchan Yu & Xing-Jie Liang

  3. National Center for International Research of Biological Targeting Diagnosis and Therapy, Guangxi Key Laboratory of Biological Targeting Diagnosis and Therapy Research, Guangxi Medical University, Nanning, 530021, China

    Hong Tan, Mengyu Zhang & Yongxiang Zhao

Authors
  1. Chanchan Yu
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  2. Kun Li
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  3. Lin Xu
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  4. Bo Li
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  5. Chunhui Li
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  7. Ziyue Li
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  10. Hong Tan
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Corresponding authors

Correspondence to Yongxiang Zhao, Yuanyu Huang or Xing-Jie Liang.

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Yu, C., Li, K., Xu, L. et al. siRNA-functionalized lanthanide nanoparticle enables efficient endosomal escape and cancer treatment. Nano Res. 15, 9160–9168 (2022). https://doi.org/10.1007/s12274-022-4573-2

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  • DOI: https://doi.org/10.1007/s12274-022-4573-2

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