Skip to main content
SpringerLink
Log in

Application of biocompatible custom ceria nanoparticles in improving the quality of liver grafts for transplantation

  • Research Article
  • Published:
Nano Research Aims and scope Submit manuscript

Abstract

Liver transplantation (LT), an ultimate and vital method for treating end-stage liver disease, is often accompanied by ischemia-reperfusion injury (IRI) resulting from warm or cold ischemia of the donor liver. Organ protection techniques are used to improve the quality of liver grafts (from retrieval to implantation). Reactive oxygen species (ROS) cause oxidative stress, which is considered a crucial factor in IRI after LT. Nano antioxidants capable of scavenging ROS alleviate IRI in multiple types of organs and tissues. In this study, we synthesized ceria nanoparticles (NPs) with antioxidant properties using a pyrolysis method and covered them with phospholipid-polyethylene glycol to improve their biocompatibility in vivo. We investigated the potential organ-protective effect of ceria NPs and the underlying mechanisms. Ceria NPs promoted liver function recovery after LT by attenuating IRI in liver grafts in vivo. The protective effect of ceria NPs on liver grafts was investigated by applying hypothermic oxygenated machine perfusion ex vivo. Ceria NPs attenuated hypoxia reoxygenation- or H2O2-induced hepatocyte injury by enhancing mitochondrial activity and ROS scavenging in vitro. These effects may be associated with the activation of the nuclear factor erythroid-derived 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1)/heme oxygenase 1 (HO-1) signaling pathway. In conclusion, ceria NPs may serve as a promising antioxidant agent for the treatment of hepatic IRI after LT.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Bao, Q. Q.; Hu, P.; Xu, Y. Y.; Cheng, T. S.; Wei, C. Y.; Pan, L. M.; Shi, J. L. Simultaneous blood-brain barrier crossing and protection for stroke treatment based on edaravone-loaded ceria nanoparticles. ACS Nano 2018, 12, 6794–6805.

    CAS  Google Scholar 

  2. Trapero-Marugán, M.; Little, E. C.; Berenguer, M. Stretching the boundaries for liver transplant in the 21st century. Lancet Gastroenterol. Hepatol. 2018, 3, 803–811.

    Google Scholar 

  3. Liu, Y.; Lu, T. F.; Zhang, C.; Xu, J.; Xue, Z. Z.; Busuttil, R. W.; Xu, N.; Xia, Q.; Kupiec-Weglinski, J. W.; Ji, H. F. Activation of YAP attenuates hepatic damage and fibrosis in liver ischemia-reperfusion injury. J. Hepatol. 2019, 71, 719–730.

    CAS  Google Scholar 

  4. van Rijn, R.; Schurink, I. J.; de Vries, Y.; van den Berg, A. P.; Cerisuelo, M. C.; Murad, S. D.; Erdmann, J. I.; Gilbo, N.; de Haas, R. J.; Heaton, N. et al. Hypothermic machine perfusion in liver transplantation—A randomized trial. N. Engl. J. Med. 2021, 384, 1391–1401.

    Google Scholar 

  5. Goikoetxea-Usandizaga, N.; Serrano-Maciá, M.; Delgado, T. C.; Simón, J.; Ramos, D. F.; Barriales, D.; Cornide, M. E.; Jiménez, M.; Pérez-Redondo, M.; Lachiondo-Ortega, S. et al. Mitochondrial bioenergetics boost macrophage activation, promoting liver regeneration in metabolically compromised animals. Hepatology 2022, 75, 550–566.

    CAS  Google Scholar 

  6. Ali, A.; Wang, A. Z.; Ribeiro, R. V. P.; Beroncal, E. L.; Baciu, C.; Galasso, M.; Gomes, B.; Mariscal, A.; Hough, O.; Brambate, E. et al. Static lung storage at 10 °C maintains mitochondrial health and preserves donor organ function. Sci. Transl. Med. 2021, 13, eabf7601.

    CAS  Google Scholar 

  7. Schlegel, A.; Porte, R. J.; Dutkowski, P. Protective mechanisms and current clinical evidence of hypothermic oxygenated machine perfusion (HOPE) in preventing post-transplant cholangiopathy. J. Hepatol. 2022, 76, 1330–1347.

    Google Scholar 

  8. Giraud, S.; Kerforne, T.; Zely, J.; Ameteau, V.; Couturier, P.; Tauc, M.; Hauet, T. The inhibition of eIF5A hypusination by GC7, a preconditioning protocol to prevent brain death-induced renal injuries in a preclinical porcine kidney transplantation model. Am. J. Transplant. 2020, 20, 3326–3340.

    CAS  Google Scholar 

  9. Kron, P.; Schlegel, A.; Mancina, L.; Clavien, P. A.; Dutkowski, P. Hypothermic oxygenated perfusion (HOPE) for fatty liver grafts in rats and humans. J. Hepatol. 2018, 68, 82–91.

    CAS  Google Scholar 

  10. Martins, R. M.; Teodoro, J. S.; Furtado, E.; Rolo, A. P.; Palmeira, C. M.; Tralhão, J. G. Recent insights into mitochondrial targeting strategies in liver transplantation. Int. J. Med. Sci. 2018, 15, 248–256.

    CAS  Google Scholar 

  11. Zhang, H. F.; Yan, Q.; Wang, X.; Chen, X.; Chen, Y.; Du, J.; Chen, L. J. The role of mitochondria in liver ischemia-reperfusion injury: From aspects of mitochondrial oxidative stress, mitochondrial fission, mitochondrial membrane permeable transport pore formation, mitophagy, and mitochondria-related protective measures. Oxid. Med. Cell. Longev. 2021, 2021, 6670579.

    Google Scholar 

  12. Ko, S. F.; Chen, Y. L.; Sung, P. H.; Chiang, J. Y.; Chu, Y. C.; Huang, C. C.; Huang, C. R.; Yip, H. K. Hepatic 31P-mggnttic resonance spectroscopy identified the impact of melatonin-pretreated mitochondria in acute liver ischaemia-reperfusion injury. J. Cell. Mol. Med. 2020, 24, 10088–10099.

    CAS  Google Scholar 

  13. Sha, Z. L.; Yang, Y. J.; Liu, R. L.; Bao, H. L.; Song, S. H.; Dong, J. F.; Guo, M.; Zhao, Y. Y.; Liu, H.; Ding, G. S. Hepatic ischemia-reperfusion injury in mice was alleviated by rac1 inhibition—More than just ROS-inhibition. J. Clin. Transl. Hepatol. 2022, 10, 42–52.

    Google Scholar 

  14. Ceni, E.; Mello, T.; Galli, A. Pathogenesis of alcoholic liver disease: Role of oxidative metabolism. World J. Gastroenterol. 2014, 20, 17756–17772.

    CAS  Google Scholar 

  15. Cannistrà, M.; Ruggiero, M.; Zullo, A.; Gallelli, G.; Serafini, S.; Maria, M.; Naso, A.; Grande, R.; Serra, R.; Nardo, B. Hepatic ischemia reperfusion injury: A systematic review of literature and the role of current drugs and biomarkers. Int. J. Surg. 2016, 33, S57–S70.

    Google Scholar 

  16. Li, S. X.; Bennett, Z. T.; Sumer, B. D.; Gao, J. M. Nano-immune-engineering approaches to advance cancer immunotherapy: Lessons from ultra-pH-sensitive nanoparticles. Acc. Chem. Res. 2020, 53, 2546–2557.

    CAS  Google Scholar 

  17. Zhang, T. R.; Tai, Z. G.; Cui, Z.; Chai, R. R.; Zhu, Q. G.; Chen, Z. J. Nano-engineered immune cells as “guided missiles” for cancer therapy. J. Control. Release 2022, 341, 60–79.

    CAS  Google Scholar 

  18. Cui, J. J.; Qin, L. F.; Zhang, J. W.; Abrahimi, P.; Li, H.; Li, G. X.; Tietjen, G. T.; Tellides, G.; Pober, J. S.; Mark Saltzman, W. Ex vivo pretreatment of human vessels with siRNA nanoparticles provides protein silencing in endothelial cells. Nat. Commun. 2017, 8, 191.

    Google Scholar 

  19. Soh, M.; Kang, D. W.; Jeong, H. G.; Kim, D.; Kim, D. Y.; Yang, W.; Song, C.; Baik, S.; Choi, I. Y.; Ki, S. K. et al. Ceria-zirconia nanoparticles as an enhanced multi-antioxidant for sepsis treatment. Angew. Chem., Int. Ed. 2017, 56, 11399–11403.

    CAS  Google Scholar 

  20. Yu, H.; Jin, F. Y.; Liu, D.; Shu, G. F.; Wang, X. J.; Qi, J.; Sun, M. C.; Yang, P.; Jiang, S. P.; Ying, X. Y. et al. ROS-responsive nano-drug delivery system combining mitochondria-targeting ceria nanoparticles with atorvastatin for acute kidney injury. Theranostics 2020, 10, 2342–2357.

    CAS  Google Scholar 

  21. Kwon, H. J.; Cha, M. Y.; Kim, D.; Kim, D. K.; Soh, M.; Shin, K.; Hyeon, T.; Mook-Jung, I. Mitochondria-targeting ceria nanoparticles as antioxidants for Alzheimer’s disease. ACS Nano 2016, 10, 2860–2870.

    CAS  Google Scholar 

  22. Kang, D. W.; Kim, C. K.; Jeong, H. G.; Soh, M.; Kim, T.; Choi, I. Y.; Ki, S. K.; Kim, D. Y.; Yang, W.; Hyeon, T. et al. Biocompatible custom ceria nanoparticles against reactive oxygen species resolve acute inflammatory reaction after intracerebral hemorrhage. Nano Res. 2017, 10, 2743–2760.

    CAS  Google Scholar 

  23. Ni, D. L.; Wei, H.; Chen, W. Y.; Bao, Q. Q.; Rosenkrans, Z. T.; Barnhart, T. E.; Ferreira, C. A.; Wang, Y. P.; Yao, H. L.; Sun, T. W. et al. Ceria nanoparticles meet hepatic ischemia-reperfusion injury: The perfect imperfection. Adv. Mater. 2019, 31, 1902956.

    CAS  Google Scholar 

  24. Wu, X.; Liu, S. Y.; Zhu, H. H.; Ma, Z. L.; Dai, X. H.; Liu, W. W. Scavenging ROS to alleviate acute liver injury by ZnO-NiO@COOH. Adv. Sci (Weinh.) 2022, 9, 2103982.

    CAS  Google Scholar 

  25. Fu, S. Y.; Chen, H. L.; Yang, W. T.; Xia, X. H.; Zhao, S.; Xu, X. N.; Ai, P.; Cai, Q. Y.; Li, X. Y.; Wang, Y. et al. ROS-targeted depression therapy via BSA-incubated ceria nanoclusters. Nano Lett. 2022, 22, 4519–4527.

    CAS  Google Scholar 

  26. Wang, M. L.; Zeng, F.; Ning, F. L.; Wang, Y. H.; Zhou, S. L.; He, J. Q.; Li, C.; Wang, C.; Sun, X. L.; Zhang, D. L. et al. Ceria nanoparticles ameliorate renal fibrosis by modulating the balance between oxidative phosphorylation and aerobic glycolysis. J. Nanobiotechnology. 2022, 20, 3.

    Google Scholar 

  27. Tanimoto, T.; Parseghian, M. H.; Nakahara, T.; Kawai, H.; Narula, N.; Kim, D.; Nishimura, R.; Weisbart, R. H.; Chan, G.; Richieri, R. A. et al. Cardioprotective effects of HSP72 administration on ischemia-reperfusion injury. J. Am. Coll. Cardiol. 2017, 70, 1479–1492.

    CAS  Google Scholar 

  28. Bian, Y. Q.; Chen, Y.; Wang, X. F.; Cui, G. Z.; Ung, C. O. L.; Lu, J. H.; Cong, W. H.; Tang, B. Q.; Lee, S. M. Y. Oxyphylla A ameliorates cognitive deficits and alleviates neuropathology via the Akt-GSK3β and Nrf2-Keap1-HO-1 pathways in vitro and in vivo murine models of Alzheimer’s disease. J. Adv. Res. 2021, 34, 1–12.

    CAS  Google Scholar 

  29. da Silva, R. T.; Machado, I. F.; Teodoro, J. S.; Panisello-Rosello, A.; Roselló-Catafau, J.; Rolo, A. P.; Palmeira, C. M. PEG35 as a preconditioning agent against hypoxia/reoxygenation injury. Int. J. Mol. Sci. 2022, 23, 1156.

    Google Scholar 

  30. Zeng, J.; Zhu, L.; Liu, J.; Zhu, T.; Xie, Z. H.; Sun, X. O.; Zhang, H. Metformin protects against oxidative stress injury induced by ischemia/reperfusion via regulation of the lncRNA-H19/miR-148a-3p/Rock2 axis. Oxid. Med. Cell. Longev. 2019, 2019, 8768327.

    Google Scholar 

  31. Chen, C. J.; Yao, W. F.; Wu, S.; Zhou, S. L.; Ge, M.; Gu, Y.; Li, X.; Chen, G. H.; Bellanti, J. A.; Zheng, S. G. et al. Crosstalk between connexin32 and mitochondrial apoptotic signaling pathway plays a pivotal role in renal ischemia reperfusion-induced acute kidney injury. Antioxid. Redox Signal. 2019, 30, 1521–1538.

    CAS  Google Scholar 

  32. Zhang, H. L.; Yang, N. Z.; He, H. Y.; Chai, J. W.; Cheng, X. X.; Zhao, H. H.; Zhou, D. H.; Teng, T. M.; Kong, X. R.; Yang, Q. et al. The zinc transporter ZIP7 (Slc39a7) controls myocardial reperfusion injury by regulating mitophagy. Basic Res. Cardiol. 2021, 116, 54.

    CAS  Google Scholar 

  33. Schlegel, A.; Graf, R.; Clavien, P. A.; Dutkowski, P. Hypothermic oxygenated perfusion (HOPE) protects from biliary injury in a rodent model of DCD liver transplantation. J. Hepatol. 2013, 59, 984–991.

    Google Scholar 

  34. Schlegel, A.; Muller, X.; Kalisvaart, M.; Muellhaupt, B.; Perera, M. T. P. R.; Isaac, J. R.; Clavien, P. A.; Muiesan, P.; Dutkowski, P. Outcomes of DCD liver transplantation using organs treated by hypothermic oxygenated perfusion before implantation. J. Hepatol. 2019, 70, 50–57.

    CAS  Google Scholar 

  35. Muller, X.; Schlegel, A.; Kron, P.; Eshmuminov, D.; Würdinger, M.; Meierhofer, D.; Clavien, P. A.; Dutkowski, P. Novel real-time prediction of liver graft function during hypothermic oxygenated machine perfusion before liver transplantation. Ann. Surg. 2019, 270, 783–790.

    Google Scholar 

  36. Lu, T. Y.; Zhang, J. B.; Cai, J. Y.; Xiao, J. Q.; Sui, X.; Yuan, X. F.; Li, R.; Li, Y.; Yao, J.; Lv, G. et al. Extracellular vesicles derived from mesenchymal stromal cells as nanotherapeutics for liver ischaemia-reperfusion injury by transferring mitochondria to modulate the formation of neutrophil extracellular traps. Biomaterials 2022, 284, 121486.

    CAS  Google Scholar 

  37. Resch, T.; Cardini, B.; Oberhuber, R.; Weissenbacher, A.; Dumfarth, J.; Krapf, C.; Boesmueller, C.; Oefner, D.; Grimm, M.; Schneeberger, S. Transplanting marginal organs in the era of modern machine perfusion and advanced organ monitoring. Front. Immunol. 2020, 11, 631.

    CAS  Google Scholar 

  38. Wang, L. H.; Li, J.; He, S.; Liu, Y.; Chen, H. T.; He, S. J.; Yin, M. X.; Zou, D. W.; Chen, S. R.; Luo, T. et al. Resolving the graft ischemia-reperfusion injury during liver transplantation at the single cell resolution. Cell Death Dis. 2021, 12, 589.

    CAS  Google Scholar 

  39. Javaherian, K.; Liu, J. F.; Wang, J. C. Nonhistone proteins HMG1 and HMG2 change the DNA helical structure. Science 1978, 199, 1345–1346.

    CAS  Google Scholar 

  40. Scaffidi, P.; Misteli, T.; Bianchi, M. E. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 2002, 418, 191–195.

    CAS  Google Scholar 

  41. Tsung, A.; Klune, J. R.; Zhang, X. H.; Jeyabalan, G.; Cao, Z. X.; Peng, X. M.; Stolz, D. B.; Geller, D. A.; Rosengart, M. R.; Billiar, T. R. HMGB1 release induced by liver ischemia involves Toll-like receptor 4-dependent reactive oxygen species production and calcium-mediated signaling. J. Exp. Med. 2007, 204, 2913–2923.

    CAS  Google Scholar 

  42. Shekaftik, S. O.; Nasirzadeh, N. 8-Hydroxy-2′-deoxyguanosine (8-OHdG) as a biomarker of oxidative DNA damage induced by occupational exposure to nanomaterials: A systematic review. Nanotoxicology 2021, 15, 850–864.

    Google Scholar 

  43. Pan, C. Y.; Yu, J. X.; Yao, Q.; Lin, N.; Lu, Z. P.; Zhang, Y.; Zhao, S. S.; Wang, Z. X.; Lei, X. N.; Tian, Y. et al. Prenatal neonicotinoid insecticides exposure, oxidative stress, and birth outcomes. Environ. Int. 2022, 163, 107180.

    CAS  Google Scholar 

  44. Ouzounidis, N.; Giakoustidis, A.; Poutahidis, T.; Angelopoulou, K.; Iliadis, S.; Chatzigiagkos, A.; Zacharioudaki, A.; Angelopoulos, S.; Papalois, A.; Papanikolaou, V. et al. Interleukin 18 binding protein ameliorates ischemia/reperfusion-induced hepatic injury in mice. Liver Transpl. 2016, 22, 237–246.

    Google Scholar 

  45. Zhang, S.; Cao, Y.; Xu, B.; Zhang, H.; Zhang, S. T.; Sun, J.; Tang, Y.; Wang, Y. H. An antioxidant nanodrug protects against hepatic ischemia-reperfusion injury by attenuating oxidative stress and inflammation. J. Mater. Chem. B, in press, https://doi.org/10.1039/D1TB02689E.

  46. Bai, H.; Wen, J.; Gong, J. P.; Wu, H.; Yuan, F. C.; Cao, D.; Wu, Y. K.; Lai, X.; Wang, M. H. Blockade of the Notch1/Jagged1 pathway in Kupffer cells aggravates ischemia-reperfusion injury of orthotopic liver transplantation in mice. Autoimmunity 2019, 52, 176–184.

    CAS  Google Scholar 

  47. Sadler, J. E. Biochemistry and genetics of von Willebrand factor. Annu. Rev. Biochem. 1998, 67, 395–424.

    CAS  Google Scholar 

  48. Yang, L.; Cao, H.; Sun, D.; Hou, B.; Lin, L.; Shen, Z. Y.; Song, H. L. Bone marrow mesenchymal stem cells combine with normothermic machine perfusion to improve rat donor liver quality—The important role of hepatic microcirculation in donation after circulatory death. Cell Tissue Res. 2020, 381, 239–254.

    CAS  Google Scholar 

  49. Chen, H.; Zheng, H. Z.; Li, T. J.; Jiang, Q. H.; Liu, S. L.; Zhou, X. X.; Ding, Y. T.; Xiang, X. W. Protective effect of oyster peptides derived from Crassostrea gigas on intestinal oxidative damage induced by cyclophosphamide in mice mediated through Nrf2-Keap1 signaling pathway. Front. Nutr. 2022, 9, 888960.

    Google Scholar 

  50. Liou, S. F.; Nguyen, T. T. N.; Hsu, J. H.; Sulistyowati, E.; Huang, S. E.; Wu, B. N.; Lin, M. C.; Yeh, J. L. The preventive effects of xanthohumol on vascular calcification induced by vitamin D3 plus nicotine. Antioxidants (Basel) 2020, 6, 956.

    Google Scholar 

Download references

Acknowledgements

This study was supported by Public Projects of Zhejiang Province (No. LGF21H030006), Major Science and Technology Projects of Hainan Province (No. ZDKJ2019009), the Zhejiang Provincial Natural Science Foundation of China (No. LZ21H180001), a Research Project of Jinan Microecological Biomedicine Shandong Laboratory (Nos. JNL-2022002A, JNL-2022007B, and JNL-2022023C), and the National Natural Science Foundation of China (No. 82000618).

Author information

Author notes

  1. Yinbiao Qiao and Jianhui Li contributed equally to this work.

Authors and Affiliations

  1. Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China

    Yinbiao Qiao, Suchen Bian, Chenyue Zhan, Jia Luo, Li Jiang, Hao Wu, Cheng Zhang, Shusen Zheng, Haiyang Xie & Penghong Song

  2. National Health Commission (NHC) Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310003, China

    Yinbiao Qiao, Jianhui Li, Suchen Bian, Jia Luo, Li Jiang, Haoyu Li, Shusen Zheng, Haiyang Xie & Penghong Song

  3. Department of Hepatobiliary and Pancreatic Surgery, Department of Liver Transplantation, Shulan (Hangzhou) Hospital, Zhejiang Shuren University School of Medicine, Hangzhou, 310015, China

    Jianhui Li

  4. The Organ Repair and Regeneration Medicine Institute of Hangzhou, Hangzhou, 310003, China

    Jianhui Li

Authors
  1. Yinbiao Qiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jianhui Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Suchen Bian
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chenyue Zhan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jia Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Li Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Haoyu Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hao Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Cheng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Shusen Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Haiyang Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Penghong Song
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Shusen Zheng, Haiyang Xie or Penghong Song.

Electronic Supplementary Material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Qiao, Y., Li, J., Bian, S. et al. Application of biocompatible custom ceria nanoparticles in improving the quality of liver grafts for transplantation. Nano Res. 16, 5176–5188 (2023). https://doi.org/10.1007/s12274-022-5071-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12274-022-5071-2

Keywords

Search

Navigation