Differential Immunomodulatory Effect of Carbon Dots Influenced by the Type of Surface Passivation Agent

  • 78 Accesses


Carbon nanodots (CDs) are often synthesized from natural sources including honey, molasses, fruits, and foods, and plant extracts simply through caramelization. They have wide biological applications especially as drug delivery vehicles and bioimaging agent due to their small size and biocompatibility. This article details the synthesis of carbon dots from carob and its derivatives by surface passivation with polyethylene glycol (PEG), polyvinyl alcohol (PVA), and alginate (ALG). We investigated the immune response against CDs and evaluated the effect of surface passivation agents on their immunomodulatory functions. CDPVA had strong anti-inflammatory activities, whereas CDALG were pro-inflammatory. CDPEG had mild anti-inflammatory activities suggesting that these CDs can be used in the drug delivery studies as inert carriers. These results showed that depending on the type of activated groups dominated on the surface, CDs exerted differential effects on the inflammatory potential of the macrophages by changing the pro-inflammatory TNFα and IL6 production levels.

This is a preview of subscription content, log in to check access.

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA

Subscribe to journal

Immediate online access to all issues from 2019. Subscription will auto renew annually.

US$ 199

This is the net price. Taxes to be calculated in checkout.

Fig. 1
Fig. 2
Fig. 3

Change history

  • 11 January 2020

    In the Published article, the article title shows “Differential Immunomodulatory Effect of Carbon Dots Influenced”. It should be “Differential Immunomodulatory Effect of Carbon Dots Influenced by the Type of Surface Passivation Agent”.



Carbon dot




Polyethylene glycol


Polyvinyl alcohol


Tumor necrosis factor-α


Interleukin 6

RAW 264.7:

Mouse macrophage cell line


Enzyme-linked immunosorbent assay




  1. 1.

    Iwalewa, E., L. McGaw, V. Naidoo, and J. Eloff. 2007. Inflammation: the foundation of diseases and disorders. A review of phytomedicines of South African origin used to treat pain and inflammatory conditions. Afr J Biotechnol 6: 2868–2885.

  2. 2.

    Broide, D.H. 2009. Immunomodulation of allergic disease. Annu Rev Med 60: 279–291.

  3. 3.

    Grivennikov, S.I., F.R. Greten, and M. Karin. 2010. Immunity, inflammation, and cancer. Cell. 140: 883–899.

  4. 4.

    Rakoff-Nahoum, S. 2006. Why cancer and inflammation? Yale J Biol Med 79: 123–130

  5. 5.

    Coussens, L.M., and Z. Werb. 2002. Inflammation and cancer. Nature. 420: 860–867.

  6. 6.

    Hancock, R.E.W., A. Nijnik, and D.J. Philpott. 2012. Modulating immunity as a therapy for bacterial infections. Nat Rev Microbiol 10: 243–254.

  7. 7.

    Kaufmann, T., and H.U. Simon. 2015. Targeting disease by immunomodulation. Cell Death Differ 22: 185–186.

  8. 8.

    Julier, Z., A.J. Park, P.S. Briquez, and M.M. Martino. 2017. Promoting tissue regeneration by modulating the immune system. Acta Biomater 53: 13–28.

  9. 9.

    Khalil, D.N., E.L. Smith, R.J. Brentjens, and J.D. Wolchok. 2016. The future of cancer treatment: immunomodulation, CARs and combination immunotherapy. Nat Rev Clin Oncol 13: 273–290.

  10. 10.

    Tan, T.-T., and L.M. Coussens. 2007. Humoral immunity, inflammation and cancer. Curr Opin Immunol 19: 209–216.

  11. 11.

    Chen, D.S., and I. Mellman. 2013. Oncology meets immunology: the cancer-immunity cycle. Immunity. 39: 1–10.

  12. 12.

    Guevara-Patino, J.A., M.J. Turk, J.D. Wolchok, and A.N. Houghton. 2003. Immunity to cancer through immune recognition of altered self: studies with melanoma. Adv Cancer Res 90: 157–177.

  13. 13.

    Valdes-Ramos, R., and A.D. Benitez-Arciniega. 2007. Nutrition and immunity in cancer. Br J Nutr 98 (Suppl 1): S127–S132.

  14. 14.

    S.K. Singh, P.P. Kulkarni, and D. Dash. 2013. Biomedical applications of carbon based nanomaterials. Bio Nanotechnol A Revolut Food, Biomed Heal Sci, eds. Debasis Bagchi, Manashi Bagchi, Hiroyoshi Moriyama, Fereidoon Shahidi, 25:443–463. Wiley Online Library.

  15. 15.

    S.C. Ray, N.R. JANA, Carbon Nanomaterials for biological and medical applications, 2017.

  16. 16.

    Cha, C., S.R. Shin, N. Annabi, M.R. Dokmeci, and A. Khademhosseini. 2013. Carbon-based nanomaterials: multifunctional materials for biomedical engineering. ACS Nano 7 (4): 2891–2897.

  17. 17.

    Shu, Y., J. Lu, Q. Mao, R. Song, X. Wang, X. Chen, and J. Wang. 2017. Ionic liquid mediated organophilic carbon dots for drug delivery and bioimaging. Carbon N Y 114: 324–333.

  18. 18.

    Mehta, V.N., S.S. Chettiar, J.R. Bhamore, S.K. Kailasa, and R.M. Patel. 2017. Green synthetic approach for synthesis of fluorescent carbon dots for lisinopril drug delivery system and their confirmations in the cells. J Fluoresc 27: 111–124.

  19. 19.

    Yuan, A.Y., B. Guo, L. Hao, and N. Liu. 2017. Doxorubicin-loaded environmentally friendly carbon dots as a novel drug delivery system for nucleus targeted cancer therapy. Colloids Surf B: Biointerfaces 159: 349–359.

  20. 20.

    Dehghani, A., S.M. Ardekani, M. Hassan, and V.G. Gomes. 2018. Collagen derived carbon quantum dots for cell imaging in 3D scaffolds via two-photon spectroscopy. Carbon N Y 131: 238–245.

  21. 21.

    Ayaz, F., M. Özge, A. Melike, and O. Rükan. 2019. Aluminum doped carbon nanodots as potent adjuvants on the mammalian macrophages. Mol Biol Rep: 1–11.

  22. 22.

    Luo, L., C. Liu, T. He, L. Zeng, J. Xing, Y. Xia, Y. Pan, C. Gong, and A. Wu. 2018. Engineered fluorescent carbon dots as promising immune adjuvants to efficiently enhance cancer immunotherapy. Nanoscale. 10: 22035–22043.

  23. 23.

    Liu, C., P. Zhang, X. Zhai, F. Tian, W. Li, J. Yang, Y. Liu, H. Wang, W. Wang, and W. Liu. 2012. Nano-carrier for gene delivery and bioimaging based on carbon dots with PEI-passivation enhanced fluorescence. Biomaterials. 33: 3604–3613.

  24. 24.

    Ke, Y., B. Garg, and Y. Ling. 2014. Waste chicken eggshell as low-cost precursor for efficient synthesis of nitrogen-doped fluorescent carbon nanodots and their multi-functional applications. RSC Adv 4: 58329–58336.

  25. 25.

    Pal, T., S. Mohiyuddin, and G. Packirisamy. 2018. Facile and green synthesis of multicolor fluorescence carbon dots from curcumin: in vitro and in vivo bioimaging and other applications. ACS Omega 3: 831–843.

  26. 26.

    Park, S.Y., H.U. Lee, E.S. Park, S.C. Lee, J.-W. Lee, S.W. Jeong, C.H. Kim, Y.-C. Lee, Y.S. Huh, and J. Lee. 2014. Photoluminescent green carbon Nanodots from food waste-derived sources: Large-scale synthesis, properties and bio-medical applications. ACS Appl Mater Interfaces 6 (5): 3365–3370.

  27. 27.

    Wang, C., D. Sun, K. Zhuo, H. Zhang, and J. Wang. 2015. Simple and green synthesis of nitrogen-, sulfur-, and phosphorus-co- doped carbon dots with tunable luminescence properties and sensing application Chunfeng. RSC Adv 4 (96): 54060–54065.

  28. 28.

    Luo, X., W. Zhang, Y. Han, X. Chen, L. Zhu, W. Tang, and J. Wang. 2018. N , S co-doped carbon dots based fl uorescent “ on-off-on ” sensor for determination of ascorbic acid in common fruits. Food Chem 258: 214–221.

  29. 29.

    Zhang, Y., Y.H. He, P.P. Cui, X.T. Feng, L. Chen, Y.Z. Yang, and X.G. Liu. 2015. Water-soluble, nitrogen-doped fluorescent carbon dots for highly sensitive and selective detection of Hg2+ in aqueous solution. RSC Adv 5 (50): 40393–40401.

  30. 30.

    Zhao, C., Y. Jiao, Z. Gao, Y. Yang, and H. Li. 2018. N, S co-doped carbon dots for temperature probe and the detection of tetracycline based on the inner filter effect. J Photochem Photobiol A Chem 367: 137–144.

  31. 31.

    Çalhan, S.D., M.Ö. Alaş, M. Aşık, F.N.D. Kaya, and R. Genç. 2018. One-pot synthesis of hydrophilic and hydrophobic fluorescent carbon dots using deep eutectic solvents as designer reaction media. J Mater Sci 53: 15362–15375.

  32. 32.

    Alas, M.O., and R. Genc. 2017. An investigation into the role of macromolecules of different polarity as passivating agent on the physical , chemical and structural properties of fluorescent carbon nanodots. J Nanopart Res 19: 185.

  33. 33.

    Yang, Q., and S.K. Lai. 2015. Anti-PEG immunity: emergence, characteristics, and unaddressed questions. Wiley Interdiscip Rev Nanomedicine Nanobiotechnology 7: 655–677.

  34. 34.

    Wan, X., J. Zhang, W. Yu, L. Shen, S. Ji, and T. Hu. 2017. Effect of protein immunogenicity and PEG size and branching on the anti-PEG immune response to PEGylated proteins. Process Biochem 52: 183–191.

  35. 35.

    Giacalone, G., N. Tsapis, L. Mousnier, H. Chacun, and E. Fattal. 2018. PLA-PEG nanoparticles improve the anti-inflammatory effect of rosiglitazone on macrophages by enhancing drug uptake compared to free rosiglitazone. Materials (Basel) 11: 1845.

  36. 36.

    Kzhyshkowska, J., A. Gudima, V. Riabov, C. Dollinger, P. Lavalle, and N.E. Vrana. 2015. Macrophage responses to implants: Prospects for personalized medicine. J Leukoc Biol 98: 953–962.

  37. 37.

    Sterzel, R.B., G.M. Eisenbach, M.W. Seiler, and J.R. Hoyer. 1983. Uptake of polyvinyl alcohol by macrophages in the glomerular mesangium of rats. Histologic and functional studies. Am J Pathol 111: 247–257

  38. 38.

    Pueyo, M.E., S. Darquy, F. Capron, and G. Reach. 1993. In vitro activation of human macrophages by alginate-polylysine microcapsules. J Biomater Sci Polym Ed 5: 197–203.

  39. 39.

    Bygd, H.C., and K.M. Bratlie. 2016. The effect of chemically modified alginates on macrophage phenotype and biomolecule transport. J Biomed Mater Res Part A 104 (7): 1707–1719.

  40. 40.

    Muñoz, L., A. Albillos, M. Nieto, E. Reyes, L. Lledó, J. Monserrat, E. Sanz, A. Hera, and M. Alvarez-Mon. 2005. Mesenteric Th1 polarization and monocyte TNF-α production: First steps to systemic inflammation in rats with cirrhosis. Hepatology. 42 (2): 411–419.

  41. 41.

    Romagnani, S. 1999. Th1/Th2 cells. Inflamm Bowel Dis 5: 285–294.

  42. 42.

    Jin, P., Y. Zhao, H. Liu, J. Chen, J. Ren, J. Jin, D. Bedognetti, S. Liu, E. Wang, F. Marincola, and D. Stroncek. 2016. Interferon-γ and tumor necrosis factor-α polarize bone marrow stromal cells uniformly to a Th1 phenotype. Sci Rep 6: 26345.

  43. 43.

    Baeten, D., N. Van Damme, F. Van Den Bosch, E. Kruithof, M. De Vos, and H. Mielants. 2001. Impaired Th1 cytokine production in spondyloarthropathy is restored by anti-TNF. Ann Rheum Dis 60 (8): 750–755.

  44. 44.

    Swain, S.L., and T. Subsets. 1995. T-cell subsets: who does the polarizing? T Curr Biol 5: 849–851.

  45. 45.

    Kimura, A., and T. Kishimoto. 2010. IL-6: regulator of Treg/Th17 balance. Eur J Immunol 40 (7): 1830–1835.

  46. 46.

    Chung, Y., S.H. Chang, G.J. Martinez, X.O. Yang, R. Nurieva, H.S. Kang, L. Ma, S.S. Watowich, A.M. Jetten, Q. Tian, and C. Dong. 2009. Critical regulation of early Th17 cell differentiation by interleukin-1 signaling. Immunity. 30: 576–587.

  47. 47.

    Dranoff, G., and D. Fearon. 2013. Tumour immunology. Curr Opin Immunol 25: 189–191.

  48. 48.

    Raval, R.R., A.B. Sharabi, A.J. Walker, C.G. Drake, and P. Sharma. 2014. Tumor immunology and cancer immunotherapy: summary of the 2013 SITC primer. J Immunother Cancer 2: 14.

  49. 49.

    Palucka, A.K., and L.M. Coussens. 2016. The basis of oncoimmunology. Cell. 164: 1233–1247.

Download references


Authors greatly appreciate the material support of Prof. Dr. Juan Anguita from CICBiogune. M.O. A. thanks to the graduate scholarship from the Council of Higher Education.

Funding Information

This study was supported by 2017–2-AP-4-2506 BAP Project of Mersin University.

Author information

F.A. and R.G. designed the study. M.O.A synthesized and characterized CDs. F.A performed the in vitro studies on macrophages. F.A and R.G analyzed the data and wrote the paper with input from all authors.

Correspondence to Furkan Ayaz or Rukan Genc.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict(s) of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

The original version of this article was revised: In the Published article, the article title shows “Differential Immunomodulatory Effect of Carbon Dots Influenced”. It should be “Differential Immunomodulatory Effect of Carbon Dots Influenced by the Type of Surface Passivation Agent”.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ayaz, F., Alas, M.O. & Genc, R. Differential Immunomodulatory Effect of Carbon Dots Influenced by the Type of Surface Passivation Agent. Inflammation (2019) doi:10.1007/s10753-019-01165-0

Download citation


  • carbon dots
  • macrophage
  • anti-inflammatory molecules
  • immunomodulation
  • adjuvants
  • immunotherapy