Optimizing surface-engineered ultra-small gold nanoparticles for highly efficient miRNA delivery to enhance osteogenic differentiation of bone mesenchymal stromal cells

Abstract

Regulation of osteogenic differentiation of bone mesenchymal stromal cells (BMSCs) plays a critical role in bone regeneration. As small non-coding RNAs, microRNAs (miRNAs) play an important role in stem cell differentiation through regulating target-mRNA expression. Unfortunately, highly efficient and safe delivery of miRNAs to BMSCs to regulate their osteogenic differentiation remains challenging. Conventional inorganic nanocrystals have shown increased toxicity owing to their larger size precluding renal clearance. Here, we developed novel, surface-engineered, ultra-small gold nanoparticles (USAuNPs, <10 nm) for use as highly efficient miR-5106-delivery systems to enable regulation of BMSC differentiation. We exploited the effects of AuNPs coated layer-by-layer with polyethylenimine (PEI) and liposomes (Lipo) to enhance miR-5106-delivery activity and subsequent BMSC differentiation capacity. The PEI- and Lipo-coated AuNPs (Au@PEI@Lipo) showed negligible cytotoxicity, good miRNA-5106-binding affinity, highly efficient delivery of miRNAs to BMSCs, and long-term miRNA expression (21 days). Additionally, compared with commercial Lipofectamine 3000 and 25 kD PEI, the optimized Au@PEI@Lipo-miR-5106 nanocomplexes significantly enhanced BMSC differentiation into osteoblast-like cells through activation of the Sox9 transcription factor. Our findings reveal a promising strategy for the rational design of ultra-small inorganic nanoparticles as highly efficient miRNA-delivery platforms for tissue regeneration and disease therapy.

This is a preview of subscription content, access via your institution.

References

  1. [1]

    Oliveira, J. M.; Rodrigues, M. T.; Silva, S. S.; Malafaya, P. B.; Gomes, M. E.; Viegas, C. A.; Dias, I. R.; Azevedo, J. T.; Mano, J. F.; Reis, R. L. Novel hydroxyapatite/chitosan bilayered scaffold for osteochondral tissue-engineering applications: Scaffold design and its performance when seeded with goat bone marrow stromal cells. Biomaterials 2006, 27, 6123–6137.

    Article  Google Scholar 

  2. [2]

    Zhu, Y.; Mao, Z. W.; Gao, C. Y. Control over the gradient differentiation of rat BMSCs on a PCL membrane with surface-immobilized alendronate gradient. Biomacromolecules 2013, 14, 342–349.

    Article  Google Scholar 

  3. [3]

    Lewis, B. P.; Burge, C. B.; Bartel, D. P. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 2005, 120, 15–20.

    Article  Google Scholar 

  4. [4]

    Stegen, S.; van Gastel, N.; Carmeliet, G. Bringing new life to damaged bone: The importance of angiogenesis in bone repair and regeneration. Bone 2015, 70, 19–27.

    Article  Google Scholar 

  5. [5]

    Li, Y.; Fan, L. K.; Liu, S. Y.; Liu, W. J.; Zhang, H.; Zhou, T.; Wu, D.; Yang, P.; Shen, L. J.; Chen, J. H. et al. The promotion of bone regeneration through positive regulation of angiogenic–osteogenic coupling using microRNA-26a. Biomaterials 2013, 34, 5048–5058.

    Article  Google Scholar 

  6. [6]

    Zhang, X. J.; Li, Y.; Chen, Y. E.; Chen, J. H.; Ma, P. X. Cell-free 3D scaffold with two-stage delivery of miRNA-26a to regenerate critical-sized bone defects. Nat. Commun. 2016, 7, 10376.

    Article  Google Scholar 

  7. [7]

    Kai, Z. S.; Pasquinelli, A. E. MicroRNA assassins: Factors that regulate the disappearance of miRNAs. Nat. Struct. Mol. Biol. 2010, 17, 5–10.

    Article  Google Scholar 

  8. [8]

    Bozzuto, G.; Molinari, A. Liposomes as nanomedical devices. Int. J. Nanomedicine 2015, 10, 975–999.

    Article  Google Scholar 

  9. [9]

    Pattni, B. S.; Chupin, V. V.; Torchilin, V. P. New developments in liposomal drug delivery. Chem. Rev. 2015, 115, 10938–10966.

    Article  Google Scholar 

  10. [10]

    Yin, H.; Kanasty, R. L.; Eltoukhy, A. A.; Vegas, A. J.; Dorkin, J. R.; Anderson, D. G. Non-viral vectors for genebased therapy. Nat. Rev. Genet. 2014, 15, 541–555.

    Article  Google Scholar 

  11. [11]

    Wang, W.; Li, W.; Ma, N.; Steinhoff, G. Non-viral gene delivery methods. Curr. Pharm. Biotechnol. 2013, 14, 46–60.

    Google Scholar 

  12. [12]

    Arote, R.; Kim, T.-H.; Kim, Y.-K.; Hwang, S.-K.; Jiang, H.-L.; Song, H.-H.; Nah, J.-W.; Cho, M.-H.; Cho, C.-S. A biodegradable poly(ester amine) based on polycaprolactone and polyethylenimine as a gene carrier. Biomaterials 2007, 28, 735–744.

    Article  Google Scholar 

  13. [13]

    Xiong, M. P.; Forrest, M. L.; Ton, G.; Zhao, A. N.; Davies, N. M.; Kwon, G. S. Poly(aspartate-g-PEI800), a polyethylenimine analogue of low toxicity and high transfection efficiency for gene delivery. Biomaterials 2007, 28, 4889–4900.

    Article  Google Scholar 

  14. [14]

    Conde, J.; Edelman, E. R.; Artzi, N. Target-responsive DNA/RNA nanomaterials for microRNA sensing and inhibition: The jack-of-all-trades in cancer nanotheranostics? Adv. Drug Deliv. Rev. 2015, 81, 169–183.

    Article  Google Scholar 

  15. [15]

    Dong, H. F.; Dai, W. H.; Ju, H. X.; Lu, H. T.; Wang, S. Y.; Xu, L. P.; Zhou, S.-F.; Zhang, Y.; Zhang, X. J. Multifunctional poly(L-lactide)–polyethylene glycol-grafted graphene quantum dots for intracellular microrna imaging and combined specificgene- targeting agents delivery for improved therapeutics. ACS Appl. Mater. Interfaces 2015, 7, 11015–11023.

    Article  Google Scholar 

  16. [16]

    Wang, X. L.; Lai, Y. X.; Ng, H. H.; Yang, Z. J.; Qin, L. Systemic drug delivery systems for bone tissue regeneration— A mini review. Curr. Pharm. Des. 2015, 21, 1575–1583.

    Article  Google Scholar 

  17. [17]

    Wang, Y. D.; Zern, B.; Gumera, C. Biomimetic Polymers and Uses Thereof. U.S. Patent 8,529,928, Sep 10, 2013.

    Google Scholar 

  18. [18]

    Ding, Y.; Jiang, Z. W.; Saha, K.; Kim, C. S.; Kim, S. T.; Landis, R. F.; Rotello, V. M. Gold nanoparticles for nucleic acid delivery. Mol. Ther. 2014, 22, 1075–1083.

    Article  Google Scholar 

  19. [19]

    Almeida, J. P. M.; Figueroa, E. R.; Drezek, R. A. Gold nanoparticle mediated cancer immunotherapy. Nanomedicine 2014, 10, 503–514.

    Google Scholar 

  20. [20]

    Austin, L. A.; Mackey, M. A.; Dreaden, E. C.; El-Sayed, M. A. The optical, photothermal, and facile surface chemical properties of gold and silver nanoparticles in biodiagnostics, therapy, and drug delivery. Arch. Toxicol. 2014, 88, 1391–1417.

    Article  Google Scholar 

  21. [21]

    Ghosh, R.; Singh, L. C.; Shohet, J. M.; Gunaratne, P. H. A gold nanoparticle platform for the delivery of functional microRNAs into cancer cells. Biomaterials 2013, 34, 807–816.

    Article  Google Scholar 

  22. [22]

    Wang, H. Y.; Jiang, Y. F.; Peng, H. G.; Chen, Y. Z.; Zhu, P. Z.; Huang, Y. Z. Recent progress in microRNA delivery for cancer therapy by non-viral synthetic vectors. Adv. Drug Deliv. Rev. 2015, 81, 142–160.

    Article  Google Scholar 

  23. [23]

    Bishop, C. J.; Tzeng, S. Y.; Green, J. J. Degradable polymercoated gold nanoparticles for co-delivery of DNA and siRNA. Acta Biomater. 2015, 11, 393–403.

    Article  Google Scholar 

  24. [24]

    Longmire, M.; Choyke, P. L.; Kobayashi, H. Clearance properties of nano-sized particles and molecules as imaging agents: Considerations and caveats. Nanomedicine 2008, 3, 703–717.

    Article  Google Scholar 

  25. [25]

    Wang, B.; He, X.; Zhang, Z. Y.; Zhao, Y. L.; Feng, W. Y. Metabolism of nanomaterials in vivo: Blood circulation and organ clearance. Acc. Chem. Res. 2013, 46, 761–769.

    Article  Google Scholar 

  26. [26]

    Karmali, P. P.; Simberg, D. Interactions of nanoparticles with plasma proteins: Implication on clearance and toxicity of drug delivery systems. Expert Opin. Drug Deliv. 2011, 8, 343–357.

    Article  Google Scholar 

  27. [27]

    Zhang, X.-D.; Wu, D.; Shen, X.; Liu, P.-X.; Yang, N.; Zhao, B.; Zhang, H.; Sun, Y.-M.; Zhang, L.-A.; Fan, F.-Y. Sizedependent in vivo toxicity of PEG-coated gold nanoparticles. Int. J. Nanomedicine 2011, 6, 2071–2081.

    Article  Google Scholar 

  28. [28]

    Zhang, X.-D.; Wu, D.; Shen, X.; Liu, P.-X.; Fan, F.-Y.; Fan, S.-J. In vivo renal clearance, biodistribution, toxicity of gold nanoclusters. Biomaterials 2012, 33, 4628–4638.

    Article  Google Scholar 

  29. [29]

    Dreaden, E. C.; Morton, S. W.; Shopsowitz, K. E.; Choi, J.-H.; Deng, Z. J.; Cho, N.-J.; Hammond, P. T. Bimodal tumor-targeting from microenvironment responsive hyaluronan layer-by-layer (LbL) nanoparticles. ACS Nano 2014, 8, 8374–8382.

    Article  Google Scholar 

  30. [30]

    Sun, Q.; Kang, Z. S.; Xue, L. J.; Shang, Y. K.; Su, Z. G.; Sun, H. B.; Ping, Q. N.; Mo, R.; Zhang, C. A collaborative assembly strategy for tumor-targeted siRNA delivery. J. Am. Chem. Soc. 2015, 137, 6000–6010.

    Article  Google Scholar 

  31. [31]

    Gao, C. B.; Vuong, J.; Zhang, Q.; Liu, Y. D.; Yin, Y. D. One-step seeded growth of Au nanoparticles with widely tunable sizes. Nanoscale 2012, 4, 2875–2878.

    Article  Google Scholar 

  32. [32]

    Link, S.; El-Sayed, M.-A. Size and temperature dependence of the plasmon absorption of colloidal gold nanoparticles. J. Phys. Chem. B 1999, 103, 4212–4217.

    Article  Google Scholar 

  33. [33]

    Lee, Y.; Lee, S.-H.; Kim, J.-S.; Maruyama, A.; Chen, X. S.; Park, T.-G. Controlled synthesis of PEI-coated gold nanoparticles using reductive catechol chemistry for siRNA delivery. J. Control. Release 2011, 155, 3–10.

    Article  Google Scholar 

  34. [34]

    Elbakry, A.; Zaky, A.; Liebl, R.; Rachel, R.; Goepferich, A.; Breunig, M. Layer-by-layer assembled gold nanoparticles for siRNA delivery. Nano Lett. 2009, 9, 2059–2064.

    Article  Google Scholar 

  35. [35]

    Fontana, L.; Pelosi, E.; Greco, P.; Racanicchi, S.; Testa, U.; Liuzzi, F.; Croce, C. M.; Brunetti, E.; Grignani, F.; Peschle, C. MicroRNAs 17–5p-20a-106a control monocytopoiesis through AML1 targeting and M-CSF receptor upregulation. Nat. Cell Biol. 2007, 9, 775–787.

    Article  Google Scholar 

  36. [36]

    Huang, X.; Gschweng, E.; Van Handel, B.; Cheng, D.; Mikkola, H. K.; Witte, O. N. Regulated expression of microRNAs-126/126* inhibits erythropoiesis from human embryonic stem cells. Blood 2011, 117, 2157–2165.

    Article  Google Scholar 

  37. [37]

    Boanini, E.; Torricelli, P.; Gazzano, M.; Della Bella, E.; Fini, M.; Bigi, A. Combined effect of strontium and zoledronate on hydroxyapatite structure and bone cell responses. Biomaterials 2014, 35, 5619–5626.

    Article  Google Scholar 

  38. [38]

    Ehlerding, E. B.; Chen, F.; Cai, W. B. Biodegradable and renal clearable inorganic nanoparticles. Adv. Sci. 2016, 3, 1500223.

    Article  Google Scholar 

  39. [39]

    Choi, H. S.; Liu, W. B.; Misra, P.; Tanaka, E.; Zimmer, J. P.; Itty Ipe, B.; Bawendi, M. G.; Frangioni, J. V. Renal clearance of quantum dots. Nat. Biotechnol. 2007, 25, 1165–1170.

    Article  Google Scholar 

  40. [40]

    Yu, M. X.; Zheng, J. Clearance pathways and tumor targeting of imaging nanoparticles. ACS Nano 2015, 9, 6655–6674.

    Article  Google Scholar 

  41. [41]

    Rana, S.; Bajaj, A.; Mout, R.; Rotello, V. M. Monolayer coated gold nanoparticles for delivery applications. Adv. Drug Deliv. Rev. 2012, 64, 200–216.

    Article  Google Scholar 

  42. [42]

    Tian, H. Y.; Guo, Z. P.; Chen, J.; Lin, L.; Xia, J. J.; Dong, X.; Chen, X. S. PEI conjugated gold nanoparticles: Efficient gene carriers with visible fluorescence. Adv. Healthc. Mater. 2012, 1, 337–341.

    Article  Google Scholar 

  43. [43]

    Shen, J. L.; Kim, H. C.; Mu, C. F.; Gentile, E.; Mai, J. H.; Wolfram, J.; Ji, L. N.; Ferrari, M.; Mao, Z. W.; Shen, H. F. Multifunctional gold nanorods for siRNA gene silencing and photothermal therapy. Adv. Healthc. Mater. 2014, 3, 1629–1637.

    Article  Google Scholar 

  44. [44]

    Valencia-Sanchez, M. A.; Liu, J. D.; Hannon, G. J.; Parker, R. Control of translation and mRNA degradation by miRNAs and siRNAs. Genes Dev. 2006, 20, 515–524.

    Article  Google Scholar 

  45. [45]

    Peng, B.; Chen, Y. M.; Leong, K. W. MicroRNA delivery for regenerative medicine. Adv. Drug Deliv. Rev. 2015, 88, 108–122.

    Article  Google Scholar 

  46. [46]

    Yang, J. P.; Zhang, Q.; Chang, H.; Cheng, Y. Y. Surfaceengineered dendrimers in gene delivery. Chem. Rev. 2015, 115, 5274–5300.

    Article  Google Scholar 

Download references

Acknowledgments

We acknowledge the valuable comments of potential reviewers. This work was supported by State Key Laboratory for Mechanical Behavior of Materials, the Scientific Research Starting Foundation from Xi’an Jiaotong University (No. DW011798N3000010), the Fundamental Research Funds for the Central Universities (No. XJJ2014090), the Natural Science Basic Research Plan in Shaanxi Province of China (No. 2015JQ5165), and National Natural Science Foundation of China (No. 51502237).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Bo Lei.

Additional information

These authors contributed equally to this work.

Electronic supplementary material

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Yu, M., Lei, B., Gao, C. et al. Optimizing surface-engineered ultra-small gold nanoparticles for highly efficient miRNA delivery to enhance osteogenic differentiation of bone mesenchymal stromal cells. Nano Res. 10, 49–63 (2017). https://doi.org/10.1007/s12274-016-1265-9

Download citation

Keywords

  • ultra-small gold nanoparticles
  • surface engineering
  • microRNA (miRNA) delivery
  • bone mesenchymal stromal cells
  • osteogenic differentiation