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Volume 21, Issue 1
  • ISSN: 1573-4137
  • E-ISSN: 1875-6786
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Abstract

Aims

Nanoparticles are important agents for targeted drug delivery to tissues or organs, or even solid tumour in certain instances. However, their surface charge distribution makes them amenable to recognition by the host immune mechanisms, especially the innate immune system, which interferes with their intended targeting, circulation life, and eventual fate in the body. We aimed to study the immunological response of iron oxide nanoparticles (Fe-NPs) and the role of the complement system in inducing an inflammatory cascade.

Background

The complement system is an important component of the innate immune system that can recognise molecular patterns on the pathogens (non-self), altered self (apoptotic and necrotic cells, and aggregated proteins such as beta-amyloid peptides), and cancer cells. It is no surprise that clusters of charge on nanoparticles are recognised by complement subcomponents, thus activating the three complement pathways: classical, alternative, and lectin.

Objective

This study aimed to examine the ability of Fe-NPs to activate the complement system and interact with macrophages .

Methods

Complement activation following exposure of Fe-NPs to macrophage-like cell line (THP-1) was analyzed by standard protocol. Real-time PCR was used for mRNA-level gene expression analysis, whereas multiplex cytokine array was used for protein-level expression analysis of cytokines and chemokines.

Results

Fe-NPs activated all three pathways to a certain extent; however, the activation of the lectin pathway was the most pronounced, suggesting that Fe-NPs bind mannan-binding lectin (MBL), a pattern recognition soluble receptor (humoral factor). MBL-mediated complement activation on the surface of Fe-NPs enhanced their uptake by THP-1 cells, in addition to dampening inflammatory cytokines, chemokines, growth factors, and soluble immune ligands.

Conclusion

Selective complement deposition (mostly the MBL pathway in this study) can make pro-inflammatory nanoparticles biocompatible and render them anti-inflammatory properties.

© 2025 Bentham Science Publishers
© 2025 The Author(s). Published by Bentham Science Publishers. This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode
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2025-01-01
2025-02-17

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References

  1. Daldrup-LinkH.E. GolovkoD. RuffellB. DeNardoD.G. CastanedaR. AnsariC. RaoJ. TikhomirovG.A. WendlandM.F. CorotC. CoussensL.M. MRI of tumor-associated macrophages with clinically applicable iron oxide nanoparticles.Clin. Cancer Res.201117175695570410.1158/1078‑0432.CCR‑10‑3420 21791632
     [Google Scholar]
  2. SinghA. PatelT. HertelJ. BernardoM. KauszA. BrennerL. Safety of ferumoxytol in patients with anemia and CKD.Am. J. Kidney Dis.200852590791510.1053/j.ajkd.2008.08.001 18824288
     [Google Scholar]
  3. AuerbachM. BallardH. Clinical use of intravenous iron: Administration, efficacy, and safety.Hematology20102010133834710.1182/asheducation‑2010.1.338 21239816
     [Google Scholar]
  4. ZanganehS. HutterG. SpitlerR. LenkovO. MahmoudiM. ShawA. PajarinenJ.S. NejadnikH. GoodmanS. MoseleyM. CoussensL.M. Daldrup-LinkH.E. Iron oxide nanoparticles inhibit tumour growth by inducing pro-inflammatory macrophage polarization in tumour tissues.Nat. Nanotechnol.2016111198699410.1038/nnano.2016.168 27668795
     [Google Scholar]
  5. PondmanK. Le GacS. KishoreU. Nanoparticle-induced immune response: Health risk versus treatment opportunity.Immunobiology2023228 2152317
     [Google Scholar]
  6. MahmoudiM. LaurentS. ShokrgozarM.A. HosseinkhaniM. Toxicity evaluations of superparamagnetic iron oxide nanoparticles: Cell “vision” versus physicochemical properties of nanoparticles.ACS Nano2011597263727610.1021/nn2021088 21838310
     [Google Scholar]
  7. AlbaneseA. TangP.S. ChanW.C.W. The effect of nanoparticle size, shape, and surface chemistry on biological systems.Annu. Rev. Biomed. Eng.201214111610.1146/annurev‑bioeng‑071811‑150124 22524388
     [Google Scholar]
  8. HaroonH.B. HunterA.C. FarhangraziZ.S. MoghimiS.M. A brief history of long circulating nanoparticles.Adv. Drug Deliv. Rev.2022188114396
     [Google Scholar]
  9. PelazB. del PinoP. MaffreP. HartmannR. GallegoM. Rivera-FernándezS. de la FuenteJ.M. NienhausG.U. ParakW.J. Surface functionalization of nanoparticles with polyethylene glycol: Effects on protein adsorption and cellular uptake.ACS Nano2015976996700810.1021/acsnano.5b01326 26079146
     [Google Scholar]
  10. VromanL. Effect of absorbed proteins on the wettability of hydrophilic and hydrophobic solids.Nature1962196485347647710.1038/196476a0 13998030
     [Google Scholar]
  11. PondmanK.M. SobikM. NayakA. TsolakiA.G. JäkelA. FlahautE. HampelS. ten HakenB. SimR.B. KishoreU. Complement activation by carbon nanotubes and its influence on the phagocytosis and cytokine response by macrophages.Nanomedicine20141061287129910.1016/j.nano.2014.02.010 24607938
     [Google Scholar]
  12. VuV.P. GiffordG.B. ChenF. et al. Immunoglobulin deposition on biomolecule corona determines complement opsonization efficiency of preclinical and clinical nanoparticles.Nat. Nanotechnol.201914326026810.1021/ja107583h 21288025
     [Google Scholar]
  13. LesniakA. FenaroliF. MonopoliM.P. ÅbergC. DawsonK.A. SalvatiA. Effects of the presence or absence of a protein corona on silica nanoparticle uptake and impact on cells.ACS Nano2012675845585710.1021/nn300223w 22721453
     [Google Scholar]
  14. DengZ.J. LiangM. MonteiroM. TothI. MinchinR.F. Nanoparticle-induced unfolding of fibrinogen promotes Mac-1 receptor activation and inflammation.Nat. Nanotechnol.201161394410.1038/nnano.2010.250 21170037
     [Google Scholar]
  15. PondmanK.M. PednekarL. PaudyalB. TsolakiA.G. KouserL. KhanH.A. ShamjiM.H. ten HakenB. StenbeckG. SimR.B. KishoreU. Innate immune humoral factors, C1q and factor H, with differential pattern recognition properties, alter macrophage response to carbon nanotubes.Nanomedicine20151182109211810.1016/j.nano.2015.06.009 26169151
     [Google Scholar]
  16. SimR.B. KishoreU. VilliersC.L. MarcheP.N. MitchellD.A. C1q binding and complement activation by prions and amyloids.Immunobiology20072124-5355362
     [Google Scholar]
  17. AlcorloM. TortajadaA. de CórdobaR.S. LlorcaO. Structural basis for the stabilization of the complement alternative pathway C3 convertase by properdin.Proc. Natl. Acad. Sci.201311033135041350910.1073/pnas.1309618110 23901101
     [Google Scholar]
  18. MarcusM. KarniM. BaranesK. LevyI. AlonN. MargelS. ShefiO. Iron oxide nanoparticles for neuronal cell applications: Uptake study and magnetic manipulations.J. Nanobiotechnology20161413710.1186/s12951‑016‑0190‑0 27179923
     [Google Scholar]
  19. BexbornF. AnderssonP.O. ChenH. NilssonB. EkdahlK.N. The tick-over theory revisited: Formation and regulation of the soluble alternative complement C3 convertase (C3(H2O)Bb).Mol. Immunol.20084523702379
     [Google Scholar]
  20. KouserL. PaudyalB. KaurA. StenbeckG. JonesL.A. AbozaidS.M. StoverC.M. FlahautE. SimR.B. KishoreU. Human properdin opsonizes nanoparticles and triggers a potent pro-inflammatory response by macrophages without Involving complement activation.Front. Immunol.20189131
     [Google Scholar]
  21. NilssonU.R. StormK.E. ElwingH. NilssonB. Conformational epitopes of C3 reflecting its mode of binding to an artificial polymer surface.Mol. Immunol.199330321121910.1016/0161‑5890(93)90050‑L 7679465
     [Google Scholar]
  22. GobelR.J. JanatovaJ. GoogeJ.M. AppleD.J. Activation of complement in human serum by some synthetic polymers used for intraocular lenses.Biomaterials19878428528810.1016/0142‑9612(87)90116‑5 3663806
     [Google Scholar]
  23. SimbergD. ParkJ.H. KarmaliP.P. ZhangW.M. MerkulovS. McCraeK. BhatiaS.N. SailorM. RuoslahtiE. Differential proteomics analysis of the surface heterogeneity of dextran iron oxide nanoparticles and the implications for their in vivo clearance.Biomaterials20093023-243926393310.1016/j.biomaterials.2009.03.056 19394687
     [Google Scholar]
  24. FujitaT. MatsushitaM. EndoY. The lectin-complement pathway - its role in innate immunity and evolution.Immunol. Rev.2004198118520210.1111/j.0105‑2896.2004.0123.x 15199963
     [Google Scholar]
  25. PengQ. LiK. SacksS. ZhouW. The role of anaphylatoxins C3a and C5a in regulating innate and adaptive immune responses.Inflamm. Allergy Drug Targets20098323624610.2174/187152809788681038 19601884
     [Google Scholar]
  26. MarkiewskiM.M. DeAngelisR.A. BenenciaF. Ricklin-LichtsteinerS.K. KoutoulakiA. GerardC. CoukosG. LambrisJ.D. Modulation of the antitumor immune response by complement.Nat. Immunol.20089111225123510.1038/ni.1655 18820683
     [Google Scholar]
  27. MoghimiS.M. Farhangrazi, ZS Just so stories: The random acts of anti-cancer nanomedicine performance.Nanomedicine2014101661166610.1016/j.nano.2014.04.011
     [Google Scholar]
  28. WangG. ChenF. BandaN.K. HolersV.M. WuL. MoghimiS.M. SimbergD. Activation of human complement system by dextran-coated iron oxide nanoparticles is not affected by dextran/Fe ratio, hydroxyl modifications, and crosslinking.Front. Immunol.2016741810.3389/fimmu.2016.00418 27777575
     [Google Scholar]
  29. KhanH.A. IbrahimK.E. AlrashoodS.T. AlameryS. AlrokayanS.H. Al-HarbiN. Al-MutaryM.G. SobkiS.H. KhanI. Immunohistochemistry of IL-1β, IL-6 and TNF-α in spleens of mice treated with gold nanoparticles.Saudi J. Biol. Sci.20202741163116810.1016/j.sjbs.2020.01.025 32256179
     [Google Scholar]
  30. IbrahimK. Al-MutaryM. BakhietA. KhanH. Histopathology of the liver, kidney, and spleen of mice exposed to gold nanoparticles.Molecules2018238184810.3390/molecules23081848 30044410
     [Google Scholar]
  31. KhanH.A. IbrahimK.E. KhanA. AlrokayanS.H. AlhomidaA.S. LeeY. Comparative evaluation of immunohistochemistry and real-time PCR for measuring proinflammatory cytokines gene expression in livers of rats treated with gold nanoparticles.Exp. Toxicol. Pathol.201668738139010.1016/j.etp.2016.05.006 27287986
     [Google Scholar]
  32. KhanH.A. IbrahimK.E. KhanA. AlrokayanS.H. AlhomidaA.S. Immunostaining of proinflammatory cytokines in renal cortex and medulla of rats exposed to gold nanoparticles.Histol. Histopathol.2017326597607 27678417
     [Google Scholar]
  33. Al-HarbiN.S. AlrashoodS.T. SiddiqiN.J. ArafahM.M. EkhzaimyA. KhanH.A. Effect of naked and PEG-coated gold nanoparticles on histopathology and cytokines expression in rat liver and kidneys.Nanomedicine202015328930210.2217/nnm‑2019‑0220 31774720
     [Google Scholar]
  34. IbrahimK.E. BakhietA.O. AwadallaM.E. KhanH.A. A priming dose protects against gold nanoparticles-induced proinflammatory cytokines mRNA expression in mice.Nanomedicine201813331332310.2217/nnm‑2017‑0332 29231780
     [Google Scholar]
  35. BrownD.M. JohnstonH. GubbinsE. StoneV. Serum enhanced cytokine responses of macrophages to silica and iron oxide particles and nanomaterials: A comparison of serum to lung lining fluid and albumin dispersions.J. Appl. Toxicol.201434111177118710.1002/jat.2998 24737200
     [Google Scholar]
  36. PaiA.B. ConnerT. McQuadeC.R. OlpJ. HicksP. Non-transferrin bound iron, cytokine activation and intracellular reactive oxygen species generation in hemodialysis patients receiving intravenous iron dextran or iron sucrose.Biometals201124460361310.1007/s10534‑011‑9409‑6 21229380
     [Google Scholar]
  37. FellL.H. ZawadaA.M. RogacevK.S. SeilerS. FliserD. HeineG.H. Distinct immunologic effects of different intravenous iron preparations on monocytes.Nephrol. Dial. Transplant.201429480982210.1093/ndt/gft524 24523357
     [Google Scholar]
  38. PondmanK.M. Salvador-MoralesC. PaudyalB. SimR.B. KishoreU. Interactions of the innate immune system with carbon nanotubes.Nanoscale Horiz.201724174186
     [Google Scholar]
  39. PondmanK.M. TsolakiA.G. PaudyalB. ShamjiM.H. SwitzerA. PathanA.A. AbozaidS.M. HakenB.T. StenbeckG. SimR.B. KishoreU. Complement deposition on nanoparticles can modulate immune responses by macrophage, B and T cells.J. Biomed. Nanotechnol.201612119721610.1166/jbn.2016.2124 27301184
     [Google Scholar]
  40. ChenP. KanehiraK. TaniguchiA. Role of toll-like receptors 3, 4 and 7 in cellular uptake and response to titanium dioxide nanoparticles.Sci. Technol. Adv. Mater.201314101500810.1088/1468‑6996/14/1/015008 27877566
     [Google Scholar]
  41. VerhoefJ.J.F. de GrootA.M. van MoorselM. RitsemaJ. BeztsinnaN. MaasC. Iron nanomedicines induce toll-like receptor activation, cytokine production and complement activation.Biomaterials2017119687710.1016/j.biomaterials.2016.11.025
     [Google Scholar]
  42. ElsabahyM. WooleyK.L. Cytokines as biomarkers of nanoparticle immunotoxicity.Chem. Soc. Rev.201342125552557610.1039/c3cs60064e 23549679
     [Google Scholar]
  43. OsugiY. HaraJ. TagawaS. TakaiK. HosoiG. MatsudaY. OhtaH. FujisakiH. KobayashiM. SakataN. Kawa-HaK. OkadaS. TawaA. Cytokine production regulating Th1 and Th2 cytokines in hemophagocytic lymphohistiocytosis.Blood199789114100410310.1182/blood.V89.11.4100 9166851
     [Google Scholar]
  44. RajananthananP. AttardG.S. SheikhN.A. MorrowW.J.W. Novel aggregate structure adjuvants modulate lymphocyte proliferation and Th1 and Th2 cytokine profiles in ovalbumin immunized mice.Vaccine1999181-214015210.1016/S0264‑410X(99)00213‑3 10501244
     [Google Scholar]
  45. AderemA. UnderhillD.M. Mechanisms of phagocytosis in macrophages.Annu. Rev. Immunol.199917159362310.1146/annurev.immunol.17.1.593 10358769
     [Google Scholar]
  46. ArturssonP. JohanssonD. SjöholmI. Receptor-mediated uptake of starch and mannan microparticles by macrophages: relative contribution of receptors for complement, immunoglobulins and carbohydrates.Biomaterials19889324124610.1016/0142‑9612(88)90091‑9 3408795
     [Google Scholar]
  47. FleitH.B. KobasiukC.D. The human monocyte-like cell line THP-1 expresses Fc gamma RI and Fc gamma RII.J. Leukoc. Biol.199149655656510.1002/jlb.49.6.556 1709200
     [Google Scholar]
  48. RaynalI. PrigentP. PeyramaureS. NajidA. RebuzziC. CorotC. Macrophage endocytosis of superparamagnetic iron oxide nanoparticles: Mechanisms and comparison of ferumoxides and ferumoxtran-10.Invest. Radiol.2004391566310.1097/01.rli.0000101027.57021.28 14701989
     [Google Scholar]
  49. BasudevP. Investigation of nanoparticles induced cell responses in the presence of innate immune factors.PhD thesis, Kingston University2018
     [Google Scholar]
  50. MahmoudiM. HofmannH. Rothen-RutishauserB. Petri-FinkA. Assessing the in vitro and in vivo toxicity of superparamagnetic iron oxide nanoparticles.Chem. Rev.201211242323233810.1021/cr2002596 22216932
     [Google Scholar]
  51. KimJ.A. LeeN. KimB.H. RheeW.J. YoonS. HyeonT. ParkT.H. Enhancement of neurite outgrowth in PC12 cells by iron oxide nanoparticles.Biomaterials201132112871287710.1016/j.biomaterials.2011.01.019 21288566
     [Google Scholar]
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Activation of the Complement Lectin Pathway by Iron Oxide Nano-particles and Induction of Pro-inflammatory Immune Response by Macrophages
Curr. Nanosci. 21, 82 (2025); https://doi.org/10.2174/0115734137270924231117112124
/content/journals/cnano/10.2174/0115734137270924231117112124
/content/journals/cnano/10.2174/0115734137270924231117112124
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  • Article Type:     Research Article
Keyword(s): chemokines; complement; cytokines; inflammation; Iron oxide nanoparticles; phagocytosis

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