Nano Research

, Volume 9, Issue 2, pp 291–305 | Cite as

Size-dependent gene delivery of amine-modified silica nanoparticles

  • Meihua Yu
  • Yuting Niu
  • Jun Zhang
  • Hongwei Zhang
  • Yannan Yang
  • Elena Taran
  • Siddharth Jambhrunkar
  • Wenyi Gu
  • Peter Thorn
  • Chengzhong YuEmail author
Research Article


Silica-based nanoparticles are promising carriers for gene delivery applications. To gain insights into the effect of particle size on gene transfection efficiency, amine-modified monodisperse Stöber spheres (NH2-SS) with diameters of 125, 230, 330, 440, and 570 nm were synthesized. The in vitro transfection efficiencies of NH2-SS for delivering plasmid DNA encoding green fluorescent protein (GFP) (pcDNA3-EGFP, abbreviated as pcDNA, 6.1 kbp) were studied in HEK293T cells. NH2-SS with a diameter of 330 nm (NH2-SS330) showed the highest GFP transfection level compared to NH2-SS particles with other sizes. The transfection efficiency was found as a compromise between the binding capacity and cellular uptake performance of NH2-SS330 and pcDNA conjugates. NH2-SS330 also demonstrated the highest transfection efficiency for plasmid DNA (pDNA) with a bigger size of 8.9 kbp. To our knowledge, this study is the first to demonstrate the significance of particle size for gene transfection efficiency in silica-based gene delivery systems. Our findings are crucial to the rational design of synthetic vectors for gene therapy.


silica nanoparticles gene delivery plasmid DNA particle sizes cellular uptake 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Supplementary material

12274_2015_909_MOESM1_ESM.pdf (2.9 mb)
Supplementary material, approximately 3022 KB.


  1. [1]
    Roy, K.; Mao, H. Q.; Huang, S. K.; Leong, K. W. Oral gene delivery with chitosan-DNA nanoparticles generates immunologic protection in a murine model of peanut allergy. Nat. Med. 1999, 5, 387–391.CrossRefGoogle Scholar
  2. [2]
    Luo, D.; Saltzman, W. M. Synthetic DNA delivery systems. Nat. Biotechnol. 2000, 18, 33–37.CrossRefGoogle Scholar
  3. [3]
    Lew, D.; Parker, S. E.; Latimer, T.; Abai, A. M.; Kuwahararundell, A.; Doh, S. G.; Yang, Z. Y.; Laface, D.; Gromkowski, S. H.; Nabel, G. J. et al. Cancer gene therapy using plasmid DNA: Pharmacokinetic study of DNA following injection in mice. Hum. Gene Ther. 1995, 6, 553–564.CrossRefGoogle Scholar
  4. [4]
    Giacca, M.; Zacchigna, S. Virus-mediated gene delivery for human gene therapy. J. Control. Release 2012, 161, 377–388.CrossRefGoogle Scholar
  5. [5]
    Mintzer, M. A.; Simanek, E. E. Nonviral vectors for gene delivery. Chem. Rev. 2009, 109, 259–302.CrossRefGoogle Scholar
  6. [6]
    Crystal, R. G. Transfer of genes to humans: Early lessons and obstacles to success. Science 1995, 270, 404–410.CrossRefGoogle Scholar
  7. [7]
    Tripathy, S. K.; Black, H. B.; Goldwasser, E.; Leiden, J. M. Immune responses to transgene-encoded proteins limit the stability of gene expression after injection of replicationdefective adenovirus vectors. Nat. Med. 1996, 2, 545–550.CrossRefGoogle Scholar
  8. [8]
    Bessis, N.; GarciaCozar, F. J.; Boissier, M. C. Immune responses to gene therapy vectors: Influence on vector function and effector mechanisms. Gene Ther. 2004, 11, S10–S17.CrossRefGoogle Scholar
  9. [9]
    Boussif, O.; Lezoualch, F.; Zanta, M. A.; Mergny, M. D.; Scherman, D.; Demeneix, B.; Behr, J. P. A versatile vector for gene and oligonucleotide transfer into cells in culture and in-vivo: Polyethylenimine. Proc. Natl. Acad. Sci. USA 1995, 92, 7297–7301.CrossRefGoogle Scholar
  10. [10]
    Zhang, S. B.; Zhi, D. F.; Huang, L. Lipid-based vectors for sirna delivery. J. Drug Target. 2012, 20, 724–735.CrossRefGoogle Scholar
  11. [11]
    Hoyer, J.; Neundorf, I. Peptide vectors for the nonviral delivery of nucleic acids. Acc. Chem. Res. 2012, 45, 1048–1056.CrossRefGoogle Scholar
  12. [12]
    Sokolova, V.; Epple, M. Inorganic nanoparticles as carriers of nucleic acids into cells. Angew. Chem., Int. Ed. 2008, 47, 1382–1395.CrossRefGoogle Scholar
  13. [13]
    Niu, Y. T.; Popat, A.; Yu, M. H.; Karmakar, S.; Gu, W. Y.; Yu, C. Z. Recent advances in the rational design of silicabased nanoparticles for gene therapy. Ther. Deliv. 2012, 3, 1217–1237.CrossRefGoogle Scholar
  14. [14]
    Radu, D. R.; Lai, C. Y.; Jeftinija, K.; Rowe, E. W.; Jeftinija, S.; Lin, V. S. Y. A polyamidoamine dendrimer-capped mesoporous silica nanosphere-based gene transfection reagent. J. Am. Chem. Soc. 2004, 126, 13216–13217.Google Scholar
  15. [15]
    Chen, A. M.; Zhang, M.; Wei, D. G.; Stueber, D.; Taratula, O.; Minko, T.; He, H. X. Co-delivery of doxorubicin and Bcl-2 sirna by mesoporous silica nanoparticles enhances the efficacy of chemotherapy in multidrug-resistant cancer cells. Small 2009, 5, 2673–2677.CrossRefGoogle Scholar
  16. [16]
    Kim, M. H.; Na, H. K.; Kim, Y. K.; Ryoo, S. R.; Cho, H. S.; Lee, K. E.; Jeon, H.; Ryoo, R.; Min, D. H. Facile synthesis of monodispersed mesoporous silica nanoparticles with ultralarge pores and their application in gene delivery. ACS Nano 2011, 5, 3568–3576.CrossRefGoogle Scholar
  17. [17]
    Kneuer, C.; Sameti, M.; Haltner, E. G.; Schiestel, T.; Schirra, H.; Schmidt, H.; Lehr, C. M. Silica nanoparticles modified with aminosilanes as carriers for plasmid DNA. Int. J. Pharm. 2000, 196, 257–261.CrossRefGoogle Scholar
  18. [18]
    Kneuer, C.; Sameti, M.; Bakowsky, U.; Schiestel, T.; Schirra, H.; Schmidt, H.; Lehr, C. M. A nonviral DNA delivery system based on surface modified silica-nanoparticles can efficiently transfect cells in vitro. Bioconjug. Chem. 2000, 11, 926–932.Google Scholar
  19. [19]
    Bharali, D. J.; Klejbor, I.; Stachowiak, E. K.; Dutta, P.; Roy, I.; Kaur, N.; Bergey, E. J.; Prasad, P. N.; Stachowiak, M. K. Organically modified silica nanoparticles: A nonviral vector for in vivo gene delivery and expression in the brain. Proc. Natl. Acad. Sci. USA 2005, 102, 11539–11544.CrossRefGoogle Scholar
  20. [20]
    Cebrián, V.; Yagüe, C.; Arruebo, M.; Martín-Saavedra, F. M.; Santamaría, J.; Vilaboa, N. On the role of the colloidal stability of mesoporous silica nanoparticles as gene delivery vectors. J. Nanopart. Res. 2011, 13, 4097–4108.CrossRefGoogle Scholar
  21. [21]
    Lin, X. Y.; Zhao, N. N.; Yan, P.; Hu, H.; Xu, F. J. The shape and size effects of polycation functionalized silica nanoparticles on gene transfection. Acta Biomater. 2015, 11, 381–392.CrossRefGoogle Scholar
  22. [22]
    Cebrián, V.; Martín-Saavedra, F.; Yagüe, C.; Arruebo, M.; Santamaría, J.; Vilaboa, N. Size-dependent transfection efficiency of pei-coated gold nanoparticles. Acta Biomater. 2011, 7, 3645–3655.CrossRefGoogle Scholar
  23. [23]
    Xu, D. M.; Yao, S. D.; Liu, Y. B.; Sheng, K. L.; Hong, J.; Gong, P. J.; Dong, L. Size-dependent properties of M-PEIs nanogels for gene delivery in cancer cells. Int. J. Pharm. 2007, 338, 291–296.CrossRefGoogle Scholar
  24. [24]
    Prabha, S.; Zhou, W. Z.; Panyam, J.; Labhasetwar, V. Size-dependency of nanoparticle-mediated gene transfection: Studies with fractionated nanoparticles. Int. J. Pharm. 2002, 244, 105–115.CrossRefGoogle Scholar
  25. [25]
    Stöber, W.; Fink, A.; Bohn, E. Controlled growth of monodisperse silica spheres in the micron size range. J. Colloid Interface Sci. 1968, 26, 62–69.CrossRefGoogle Scholar
  26. [26]
    Yamada, H.; Loretz, B.; Lehr, C. M. Design of starchgraft- PEI polymers: An effective and biodegradable gene delivery platform. Biomacromolecules 2014, 15, 1753–1761.CrossRefGoogle Scholar
  27. [27]
    Revet, B.; Fourcade, A. Short unligated sticky ends enable the observation of circularised DNA by atomic force and electron microscopies. Nucleic Acids Res. 1998, 26, 2092–2097.CrossRefGoogle Scholar
  28. [28]
    Jung, H. S.; Moon, D. S.; Lee, J. K. Quantitative analysis and efficient surface modification of silica nanoparticles. J. Nanomater. 2012, 2012, Article ID593471.Google Scholar
  29. [29]
    Izak-Nau, E.; Voetz, M.; Eiden, S.; Duschl, A.; Puntes, V. F. Altered characteristics of silica nanoparticles in bovine and human serum: The importance of nanomaterial characterization prior to its toxicological evaluation. Part. Fibre Toxicol. 2013, 10, 56.CrossRefGoogle Scholar
  30. [30]
    Yu, M. H.; Jambhrunkar, S.; Thorn, P.; Chen, J. Z.; Gu, W. Y.; Yu, C. Z. Hyaluronic acid modified mesoporous silica nanoparticles for targeted drug delivery to CD44-overexpressing cancer cells. Nanoscale 2013, 5, 178–183.CrossRefGoogle Scholar
  31. [31]
    Izumisawa, T.; Hattori, Y.; Date, M.; Toma, K.; Maitani, Y. Cell line-dependent internalization pathways determine DNA transfection efficiency of decaarginine-peg-lipid. Int. J. Pharm. 2011, 404, 264–270.CrossRefGoogle Scholar
  32. [32]
    Yuan, H. Y.; Li, J.; Bao, G.; Zhang, S. L. Variable nanoparticle-cell adhesion strength regulates cellular uptake. Phys. Rev. Lett. 2010, 105, 138101.CrossRefGoogle Scholar
  33. [33]
    Lu, F.; Wu, S. H.; Hung, Y.; Mou, C. Y. Size effect on cell uptake in well-suspended, uniform mesoporous silica nanoparticles. Small 2009, 5, 1408–1413.CrossRefGoogle Scholar
  34. [34]
    Luo, D.; Saltzman, W. M. Enhancement of transfection by physical concentration of DNA at the cell surface. Nat. Biotechnol. 2000, 18, 893–895.CrossRefGoogle Scholar
  35. [35]
    Luo, D.; Han, E.; Belcheva, N.; Saltzman, W. M. A selfassembled, modular DNA delivery system mediated by silica Nanoparticles. J. Control. Release 2004, 95, 333–341.CrossRefGoogle Scholar
  36. [36]
    Slowing, I. I.; Vivero-Escoto, J. L.; Wu, C. W.; Lin, V. S. Y. Mesoporous silica nanoparticles as controlled release drug delivery and gene transfection carriers. Adv. Drug Deliv. Rev. 2008, 60, 1278–1288.CrossRefGoogle Scholar
  37. [37]
    Zou, S. M.; Erbacher, P.; Remy, J. S.; Behr, J. P. Systemic linear polyethylenimine (L-PEI)-mediated gene delivery in the mouse. J. Gene Med. 2000, 2, 128–134.CrossRefGoogle Scholar
  38. [38]
    Ahn, S.; Seo, E.; Kim, K.; Lee, S. J. Controlled cellular uptake and drug efficacy of nanotherapeutics. Sci. Rep. 2013, 3, 1997.Google Scholar
  39. [39]
    Roy, I.; Ohulchanskyy, T. Y.; Bharali, D. J.; Pudavar, H. E.; Mistretta, R. A.; Kaur, N.; Prasad, P. N. Optical tracking of organically modified silica nanoparticles as DNA carriers: A nonviral, nanomedicine approach for gene delivery. Proc. Natl. Acad. Sci. USA 2005, 102, 279–284.CrossRefGoogle Scholar
  40. [40]
    Aaij, C.; Borst, P. The gel electrophoresis of DNA. Biochim. Biophys. Acta 1972, 269, 192–200.CrossRefGoogle Scholar
  41. [41]
    Zhu, J.; Tang, J. W.; Zhao, L. Z.; Zhou, X. F.; Wang, Y. H.; Yu, C. Z. Ultrasmall, well-dispersed, hollow siliceous spheres with enhanced endocytosis properties. Small 2010, 6, 276–282.CrossRefGoogle Scholar
  42. [42]
    Zhang, Y. Y.; Hu, L.; Yu, D. H.; Gao, C. Y. Influence of silica particle internalization on adhesion and migration of human dermal fibroblasts. Biomaterials 2010, 31, 8465–8474.CrossRefGoogle Scholar
  43. [43]
    Yin, W. X.; Xiang, P.; Li, Q. L. Investigations of the effect of DNA size in transient transfection assay using dual luciferase system. Anal. Biochem. 2005, 346, 289–294.CrossRefGoogle Scholar
  44. [44]
    Walczyk, D.; Bombelli, F. B.; Monopoli, M. P.; Lynch, I.; Dawson, K. A. What the cell “sees” in bionanoscience. J. Am. Chem. Soc. 2010, 132, 5761–5768.CrossRefGoogle Scholar
  45. [45]
    Lynch, I.; Cedervall, T.; Lundqvist, M.; Cabaleiro-Lago, C.; Linse, S.; Dawson, K. A. The nanoparticle-protein complex as a biological entity; a complex fluids and surface science challenge for the 21st century. Adv. Colloid Interface Sci. 2007, 134–135, 167–174.CrossRefGoogle Scholar

Copyright information

© Tsinghua University Press and Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Meihua Yu
    • 1
  • Yuting Niu
    • 1
  • Jun Zhang
    • 1
  • Hongwei Zhang
    • 1
  • Yannan Yang
    • 1
  • Elena Taran
    • 1
    • 2
  • Siddharth Jambhrunkar
    • 1
  • Wenyi Gu
    • 1
  • Peter Thorn
    • 3
  • Chengzhong Yu
    • 1
    Email author
  1. 1.Australian Institute for Bioengineering and NanotechnologyThe University of QueenslandBrisbane QLDAustralia
  2. 2.Australian National Fabrication Facility-QLD NodeBrisbaneAustralia
  3. 3.School of Biomedical SciencesThe University of QueenslandBrisbaneAustralia

Personalised recommendations