Targeting Reactive Oxygen Species-dominant Neutrophil Extracellular Trap Formation in Immunothrombosis: A Perspective on the Dual-functional Potential of Nanoceria
Abstract
Sepsis-induced immunothrombosis is driven in part by dysregulated neutrophil extracellular traps (NETs), yet existing therapies fail to adequately address the oxidative checkpoints that initiate this cascade.
This mechanistic Perspective proposes a paradigm shift toward dual-functional inorganic nanomedicine aimed at modulating both inflammation and coagulation. We discuss emerging evidence supporting a “prevention-plus-clearance” strategy employing PEGylated cerium oxide nanoparticles (nanoceria) surface-grafted with DNase I.
The inorganic core functions as a prolonged superoxide dismutase–like redox buffer through the regenerative Ce³⁺/Ce⁴⁺ cycle, thereby attenuating reactive oxygen species (ROS)-dominant NETosis pathways rather than universally blocking NET formation. In parallel, the surface-immobilized DNase I facilitates enzymatic degradation of extracellular chromatin scaffolds. We hypothesize that this bio-inorganic combination may address the biphasic nature of sepsis pathogenesis by limiting NET initiation while promoting microvascular de-obstruction.
Finally, we outline a translational roadmap required to validate this “circuit-breaker” strategy in vivo, positioning the cerium–NETosis axis as a promising frontier in the management of sepsis-associated coagulopathy.
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8. Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, et al. Neutrophil extracellular traps kill bacteria. Science. 2004;303(5663):1532-5.
9. Papayannopoulos V. Neutrophil extracellular traps in immunity and disease. Nat Rev Immunol. 2018;18(2):134-47.
10. Fuchs TA, Abed U, Goosmann C, Hurwitz R, Schulze I, Wahn V, et al. Novel cell death program leads to neutrophil extracellular traps. J Cell Biol. 2007;176(2):231-41.
11. Li P, Li M, Lindberg MR, Kennett MJ, Xiong N, Wang Y. PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps. J Exp Med. 2010;207(9):1853-62.
12. Fuchs TA, Brill A, Duerschmied D, Schatzberg D, Monestier M, Myers DD, Jr., et al. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci U S A. 2010;107(36):15880-5.
13. Long AT, Kenne E, Jung R, Fuchs TA, Renné T. Contact system revisited: an interface between inflammation, coagulation, and innate immunity. J Thromb Haemost. 2016;14(3):427-37.
14. Martinod K, Wagner DD. Thrombosis: tangled up in NETs. Blood. 2014;123(18):2768-76.
15. Espiritu A, O’Sullivan KM. A Web of Challenges: The Therapeutic Struggle to Target NETs in Disease. International Journal of Molecular Sciences [Internet]. 2025; 26(10):[4773 p.].
16. Nelson BC, Johnson ME, Walker ML, Riley KR, Sims CM. Antioxidant Cerium Oxide Nanoparticles in Biology and Medicine. Antioxidants (Basel). 2016;5(2).
17. Sanni K, Ena G, Sanket K, Anupam J. Neutrophil Extracellular Traps: Formation and Involvement in Disease Progression. Iranian Journal of Allergy, Asthma and Immunology. 2018;17(3).
18. Yipp BG, Kubes P. NETosis: how vital is it? Blood. 2013;122(16):2784-94.
19. Papayannopoulos V, Metzler KD, Hakkim A, Zychlinsky A. Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps. J Cell Biol. 2010;191(3):677-91.
20. Stoiber W, Obermayer A, Steinbacher P, Krautgartner WD. The Role of Reactive Oxygen Species (ROS) in the Formation of Extracellular Traps (ETs) in Humans. Biomolecules. 2015;5(2):702-23.
21. Celardo I, Pedersen JZ, Traversa E, Ghibelli L. Pharmacological potential of cerium oxide nanoparticles. Nanoscale. 2011;3(4):1411-20.
22. Korsvik C, Patil S, Seal S, Self WT. Superoxide dismutase mimetic properties exhibited by vacancy engineered ceria nanoparticles. Chem Commun (Camb). 2007(10):1056-8.
23. Pirmohamed T, Dowding JM, Singh S, Wasserman B, Heckert E, Karakoti AS, et al. Nanoceria exhibit redox state-dependent catalase mimetic activity. Chem Commun (Camb). 2010;46(16):2736-8.
24. Das M, Patil S, Bhargava N, Kang JF, Riedel LM, Seal S, et al. Auto-catalytic ceria nanoparticles offer neuroprotection to adult rat spinal cord neurons. Biomaterials. 2007;28(10):1918-25.
25. Dich H, Abou Rjeily R, Rath G, Berthet M, Dayde-Cazals B, Berret JF, et al. Dual-functional cerium oxide nanoparticles with antioxidant and DNase I activities to prevent and degrade neutrophil extracellular traps. Front Immunol. 2025;16:1693809.
26. Baryshev AS ea. Effect of cerium and selenium nanoparticles on functional activity of neutrophils in vitro. Opera Med Physiol. 2023;10(4):24-35.
27. Ernst LM, Puntes V. How Does Immunomodulatory Nanoceria Work? ROS and Immunometabolism. Frontiers in Immunology. 2022;Volume 13 - 2022.
28. Ren X, Chen D, Wang Y, Li H, Zhang Y, Chen H, et al. Nanozymes-recent development and biomedical applications. J Nanobiotechnology. 2022;20(1):92.
29. Sadidi H, Hooshmand S, Ahmadabadi A, Javad Hoseini S, Baino F, Vatanpour M, et al. Cerium Oxide Nanoparticles (Nanoceria): Hopes in Soft Tissue Engineering. Molecules [Internet]. 2020; 25(19):[4559 p.].
30. Radomski A, Jurasz P, Alonso-Escolano D, Drews M, Morandi M, Malinski T, et al. Nanoparticle-induced platelet aggregation and vascular thrombosis. Br J Pharmacol. 2005;146(6):882-93.
31. Bihari P, Holzer M, Praetner M, Fent J, Lerchenberger M, Reichel CA, et al. Single-walled carbon nanotubes activate platelets and accelerate thrombus formation in the microcirculation. Toxicology. 2010;269(2-3):148-54.
32. Fuchs TA, Brill A, Duerschmied D, Schatzberg D, Monestier M, Myers DD, et al. Extracellular DNA traps promote thrombosis. Proceedings of the National Academy of Sciences. 2010;107(36):15880-5.
33. Fröhlich E. The role of surface charge in cellular uptake and cytotoxicity of medical nanoparticles. Int J Nanomedicine. 2012;7:5577-91.
34. Hwang TL, Aljuffali IA, Hung CF, Chen CH, Fang JY. The impact of cationic solid lipid nanoparticles on human neutrophil activation and formation of neutrophil extracellular traps (NETs). Chem Biol Interact. 2015;235:106-14.
35. Raghavan P, Perez CA, Sorrentino TA, Kading JC, Finbloom JA, Desai TA. Physicochemical Design of Nanoparticles to Interface with and Degrade Neutrophil Extracellular Traps. ACS Appl Mater Interfaces. 2025;17(6):8862-74.
36. Nelson BC, Johnson ME, Walker ML, Riley KR, Sims CM. Antioxidant Cerium Oxide Nanoparticles in Biology and Medicine. Antioxidants [Internet]. 2016; 5(2):[15 p.].
37. Lee SS, Song W, Cho M, Puppala HL, Nguyen P, Zhu H, et al. Antioxidant Properties of Cerium Oxide Nanocrystals as a Function of Nanocrystal Diameter and Surface Coating. ACS Nano. 2013;7(11):9693-703.
38. Chigurupati S, Mughal MR, Okun E, Das S, Kumar A, McCaffery M, et al. Effects of cerium oxide nanoparticles on the growth of keratinocytes, fibroblasts and vascular endothelial cells in cutaneous wound healing. Biomaterials. 2013;34(9):2194-201.
39. Mahmoudi M, Landry MP, Moore A, Coreas R. The protein corona from nanomedicine to environmental science. Nature Reviews Materials. 2023;8(7):422-38.
40. Deuker MFS, Mailänder V, Morsbach S, Landfester K. Anti-PEG antibodies enriched in the protein corona of PEGylated nanocarriers impact the cell uptake. Nanoscale Horizons. 2023;8(10):1377-85.
2. Rudd KE, Johnson SC, Agesa KM, Shackelford KA, Tsoi D, Kievlan DR, et al. Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study. Lancet. 2020;395(10219):200-11.
3. Aklilu A, Lai MS, Jiang Z, Yip SP, Huang CL. Immunothrombosis in Sepsis: Cellular Crosstalk, Molecular Triggers, and Therapeutic Opportunities-A Review. Int J Mol Sci. 2025;26(13).
4. Iba T, Levy JH. Inflammation and thrombosis: roles of neutrophils, platelets and endothelial cells and their interactions in thrombus formation during sepsis. J Thromb Haemost. 2018;16(2):231-41.
5. Butt SP, Kakar V, Kumar A, Razzaq N, Saleem Y, Ali B, et al. Heparin resistance management during cardiac surgery: a literature review and future directions. J Extra Corpor Technol. 2024;56(3):136-44.
6. Levy JH, Connors JM. Heparin Resistance - Clinical Perspectives and Management Strategies. N Engl J Med. 2021;385(9):826-32.
7. Marshall JC. Why have clinical trials in sepsis failed? Trends Mol Med. 2014;20(4):195-203.
8. Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, et al. Neutrophil extracellular traps kill bacteria. Science. 2004;303(5663):1532-5.
9. Papayannopoulos V. Neutrophil extracellular traps in immunity and disease. Nat Rev Immunol. 2018;18(2):134-47.
10. Fuchs TA, Abed U, Goosmann C, Hurwitz R, Schulze I, Wahn V, et al. Novel cell death program leads to neutrophil extracellular traps. J Cell Biol. 2007;176(2):231-41.
11. Li P, Li M, Lindberg MR, Kennett MJ, Xiong N, Wang Y. PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps. J Exp Med. 2010;207(9):1853-62.
12. Fuchs TA, Brill A, Duerschmied D, Schatzberg D, Monestier M, Myers DD, Jr., et al. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci U S A. 2010;107(36):15880-5.
13. Long AT, Kenne E, Jung R, Fuchs TA, Renné T. Contact system revisited: an interface between inflammation, coagulation, and innate immunity. J Thromb Haemost. 2016;14(3):427-37.
14. Martinod K, Wagner DD. Thrombosis: tangled up in NETs. Blood. 2014;123(18):2768-76.
15. Espiritu A, O’Sullivan KM. A Web of Challenges: The Therapeutic Struggle to Target NETs in Disease. International Journal of Molecular Sciences [Internet]. 2025; 26(10):[4773 p.].
16. Nelson BC, Johnson ME, Walker ML, Riley KR, Sims CM. Antioxidant Cerium Oxide Nanoparticles in Biology and Medicine. Antioxidants (Basel). 2016;5(2).
17. Sanni K, Ena G, Sanket K, Anupam J. Neutrophil Extracellular Traps: Formation and Involvement in Disease Progression. Iranian Journal of Allergy, Asthma and Immunology. 2018;17(3).
18. Yipp BG, Kubes P. NETosis: how vital is it? Blood. 2013;122(16):2784-94.
19. Papayannopoulos V, Metzler KD, Hakkim A, Zychlinsky A. Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps. J Cell Biol. 2010;191(3):677-91.
20. Stoiber W, Obermayer A, Steinbacher P, Krautgartner WD. The Role of Reactive Oxygen Species (ROS) in the Formation of Extracellular Traps (ETs) in Humans. Biomolecules. 2015;5(2):702-23.
21. Celardo I, Pedersen JZ, Traversa E, Ghibelli L. Pharmacological potential of cerium oxide nanoparticles. Nanoscale. 2011;3(4):1411-20.
22. Korsvik C, Patil S, Seal S, Self WT. Superoxide dismutase mimetic properties exhibited by vacancy engineered ceria nanoparticles. Chem Commun (Camb). 2007(10):1056-8.
23. Pirmohamed T, Dowding JM, Singh S, Wasserman B, Heckert E, Karakoti AS, et al. Nanoceria exhibit redox state-dependent catalase mimetic activity. Chem Commun (Camb). 2010;46(16):2736-8.
24. Das M, Patil S, Bhargava N, Kang JF, Riedel LM, Seal S, et al. Auto-catalytic ceria nanoparticles offer neuroprotection to adult rat spinal cord neurons. Biomaterials. 2007;28(10):1918-25.
25. Dich H, Abou Rjeily R, Rath G, Berthet M, Dayde-Cazals B, Berret JF, et al. Dual-functional cerium oxide nanoparticles with antioxidant and DNase I activities to prevent and degrade neutrophil extracellular traps. Front Immunol. 2025;16:1693809.
26. Baryshev AS ea. Effect of cerium and selenium nanoparticles on functional activity of neutrophils in vitro. Opera Med Physiol. 2023;10(4):24-35.
27. Ernst LM, Puntes V. How Does Immunomodulatory Nanoceria Work? ROS and Immunometabolism. Frontiers in Immunology. 2022;Volume 13 - 2022.
28. Ren X, Chen D, Wang Y, Li H, Zhang Y, Chen H, et al. Nanozymes-recent development and biomedical applications. J Nanobiotechnology. 2022;20(1):92.
29. Sadidi H, Hooshmand S, Ahmadabadi A, Javad Hoseini S, Baino F, Vatanpour M, et al. Cerium Oxide Nanoparticles (Nanoceria): Hopes in Soft Tissue Engineering. Molecules [Internet]. 2020; 25(19):[4559 p.].
30. Radomski A, Jurasz P, Alonso-Escolano D, Drews M, Morandi M, Malinski T, et al. Nanoparticle-induced platelet aggregation and vascular thrombosis. Br J Pharmacol. 2005;146(6):882-93.
31. Bihari P, Holzer M, Praetner M, Fent J, Lerchenberger M, Reichel CA, et al. Single-walled carbon nanotubes activate platelets and accelerate thrombus formation in the microcirculation. Toxicology. 2010;269(2-3):148-54.
32. Fuchs TA, Brill A, Duerschmied D, Schatzberg D, Monestier M, Myers DD, et al. Extracellular DNA traps promote thrombosis. Proceedings of the National Academy of Sciences. 2010;107(36):15880-5.
33. Fröhlich E. The role of surface charge in cellular uptake and cytotoxicity of medical nanoparticles. Int J Nanomedicine. 2012;7:5577-91.
34. Hwang TL, Aljuffali IA, Hung CF, Chen CH, Fang JY. The impact of cationic solid lipid nanoparticles on human neutrophil activation and formation of neutrophil extracellular traps (NETs). Chem Biol Interact. 2015;235:106-14.
35. Raghavan P, Perez CA, Sorrentino TA, Kading JC, Finbloom JA, Desai TA. Physicochemical Design of Nanoparticles to Interface with and Degrade Neutrophil Extracellular Traps. ACS Appl Mater Interfaces. 2025;17(6):8862-74.
36. Nelson BC, Johnson ME, Walker ML, Riley KR, Sims CM. Antioxidant Cerium Oxide Nanoparticles in Biology and Medicine. Antioxidants [Internet]. 2016; 5(2):[15 p.].
37. Lee SS, Song W, Cho M, Puppala HL, Nguyen P, Zhu H, et al. Antioxidant Properties of Cerium Oxide Nanocrystals as a Function of Nanocrystal Diameter and Surface Coating. ACS Nano. 2013;7(11):9693-703.
38. Chigurupati S, Mughal MR, Okun E, Das S, Kumar A, McCaffery M, et al. Effects of cerium oxide nanoparticles on the growth of keratinocytes, fibroblasts and vascular endothelial cells in cutaneous wound healing. Biomaterials. 2013;34(9):2194-201.
39. Mahmoudi M, Landry MP, Moore A, Coreas R. The protein corona from nanomedicine to environmental science. Nature Reviews Materials. 2023;8(7):422-38.
40. Deuker MFS, Mailänder V, Morsbach S, Landfester K. Anti-PEG antibodies enriched in the protein corona of PEGylated nanocarriers impact the cell uptake. Nanoscale Horizons. 2023;8(10):1377-85.
| Files | ||
| Issue | Articles in Press | |
| Section | Short Perspective | |
| Keywords | ||
| Cerium oxide DNase I Immunothrombosis Neutrophil Reactive oxygen species | ||
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How to Cite
1.
Ebrahim pour M, Moridikia A, Salimi-Sabour E. Targeting Reactive Oxygen Species-dominant Neutrophil Extracellular Trap Formation in Immunothrombosis: A Perspective on the Dual-functional Potential of Nanoceria. Iran J Allergy Asthma Immunol. 2026;:1-7.
