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Multifunctional RGD coated a single-atom iron nanozyme: A highly selective approach to inducing ferroptosis and enhancing immunotherapy for pancreatic cancer

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Abstract

Nanozyme is a new promising approach to cancer therapy for its ability to induce ferroptosis by activating H2O2 via a traditional radical pathway and enhance cancer immunotherapy. However, short half-life period of hydroxyl radical (·OH) results in unsatisfied effectiveness. Herein, we synthesized a single-atom iron nanozyme (Fe-SAzyme), which can activate H2O2 via a non-radical pathway to generate Fe-based reactive oxygen species (ROS) (O=FeO3=O) for promoting the ferroptosis of pancreatic cancer cells. This Fe-SAzyme could be specifically phagocytosed by pancreatic cancer cells, increasing ROS levels and inhibiting glutathione (GSH) synthesis, which activates ferroptosis. Tumor magnetic resonance imaging (MRI) showed decreased T2 signal after intravenous injection of RGD@Fe-AC (AC = activated carbon). Moreover, RGD@Fe-AC promoted dendritic cell (DC) maturation, overcame Treg-mediated immunosuppression, activated T cells to trigger adaptive immune responses, and enhanced the efficacy of α-PD-L1 immunotherapy. Our research demonstrated that RGD@Fe-AC provided a straightforward, easily implemented, and selective approach for pancreatic cancer treatment and immunotherapy.

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References

  1. Shi, J. J.; Kantoff, P. W.; Wooster, R.; Farokhzad, O. C. Cancer nanomedicine: Progress, challenges and opportunities. Nat. Rev. Cancer 2017, 17, 20–37.

    Article  PubMed  CAS  Google Scholar 

  2. Wilhelm, S.; Tavares, A. J.; Dai, Q.; Ohta, S.; Audet, J.; Dvorak, H. F.; Chan, W. C. W. Analysis of nanoparticle delivery to tumours. Nat. Rev. Mater. 2016, 1, 16014.

    Article  ADS  CAS  Google Scholar 

  3. Ranji-Burachaloo, H.; Gurr, P. A.; Dunstan, D. E.; Qiao, G. G. Cancer treatment through nanoparticle-facilitated fenton reaction. ACS Nano 2018, 12, 11819–11837.

    Article  PubMed  CAS  Google Scholar 

  4. Wen, Q. R.; Liu, J.; Kang, R.; Zhou, B. R.; Tang, D. L. The release and activity of HMGB1 in ferroptosis. Biochem. Biophys. Res. Commun. 2019, 510, 278–283.

    Article  PubMed  CAS  Google Scholar 

  5. Zhang, Z. J.; Zhang, X. H.; Liu, B. W.; Liu, J. W. Molecular imprinting on inorganic nanozymes for hundred-fold enzyme specificity. J. Am. Chem. Soc. 2017, 139, 5412–5419.

    Article  PubMed  CAS  Google Scholar 

  6. Liu, J. M.; Wang, A. Z.; Liu, S. H.; Yang, R. Q.; Wang, L. W.; Gao, F.; Zhou, H. G.; Yu, X.; Liu, J.; Chen, C. Y. A titanium nitride nanozyme for pH-responsive and irradiation-enhanced cascade-catalytic tumor therapy. Angew. Chem., Int. Ed. 2021, 60, 25328–25338.

    Article  CAS  Google Scholar 

  7. Zhang, R. F.; Xue, B.; Tao, Y. H.; Zhao, H. Q.; Zhang, Z. X.; Wang, X. N.; Zhou, X. Y.; Jiang, B.; Yang, Z. L.; Yan, X. Y. et al. Edge-site engineering of defective Fe-N4 nanozymes with boosted catalase-like performance for retinal vasculopathies. Adv. Mater. 2022, 34, 2205324.

    Article  CAS  Google Scholar 

  8. Lu, X. Y.; Gao, S. S.; Lin, H.; Shi, J. L. Single-atom catalysts for nanocatalytic tumor therapy. Small 2021, 17, 2004467.

    Article  CAS  Google Scholar 

  9. Chen, Y. J.; Jiang, B.; Hao, H. G.; Li, H. J.; Qiu, C. Y.; Liang, X.; Qu, Q. Y.; Zhang, Z. D.; Gao, R.; Duan, D. M. et al. Atomic-level regulation of cobalt single-atom nanozymes: Engineering high-efficiency catalase mimics. Angew. Chem., Int. Ed. 2023, 62, e202301879.

    Article  CAS  Google Scholar 

  10. Ryan, D. P.; Hong, T. S.; Bardeesy, N. Pancreatic adenocarcinoma. N. Engl. J. Med. 2014, 371, 1039–1049.

    Article  PubMed  CAS  Google Scholar 

  11. Kamisawa, T.; Wood, L. D.; Itoi, T.; Takaori, K. Pancreatic cancer. Lancet 2016, 388, 73–85.

    Article  PubMed  CAS  Google Scholar 

  12. Musa, M. Single- cell analysis on stromal fibroblasts in the microenvironment of solid tumours. Adv. Med. Sci. 2020, 65, 163–169.

    Article  PubMed  CAS  Google Scholar 

  13. Vincent, A.; Herman, J.; Schulick, R.; Hruban, R. H.; Goggins, M. Pancreatic cancer. Lancet 2011, 378, 607–620.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Gonzalez, H.; Hagerling, C.; Werb, Z. Roles of the immune system in cancer: From tumor initiation to metastatic progression. Genes Dev. 2018, 32, 1267–1284.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Tanaka, A.; Sakaguchi, S. Regulatory T cells in cancer immunotherapy. Cell Res. 2017, 27, 109–118.

    Article  PubMed  CAS  Google Scholar 

  16. Clark, C. E.; Beatty, G. L.; Vonderheide, R. H. Immunosurveillance of pancreatic adenocarcinoma: Insights from genetically engineered mouse models of cancer. Cancer Lett. 2009, 279, 1–7.

    Article  PubMed  CAS  Google Scholar 

  17. Thomas, N.; Dionysiou, D. D.; Pillai, S. C. Heterogeneous Fenton catalysts: A review of recent advances. J. Hazard Mater. 2021, 404, 124082.

    Article  PubMed  CAS  Google Scholar 

  18. Li, J. J.; Ke, W. D.; Wang, L.; Huang, M. M.; Yin, W.; Zhang, P.; Chen, Q. X.; Ge, Z. S. Self-sufficing H2O2-responsive nanocarriers through tumor-specific H2O2 production for synergistic oxidation-chemotherapy. J. Control. Release 2016, 225, 64–74.

    Article  PubMed  CAS  Google Scholar 

  19. Zeng, F. T.; Tang, L. G.; Zhang, Q. Y.; Shi, C. R.; Huang, Z. C.; Nijiati, S.; Chen, X. Y.; Zhou, Z. J. Coordinating the mechanisms of action of ferroptosis and the photothermal effect for cancer theranostics. Angew. Chem., Int. Ed. 2022, 61, e202112925.

    Article  ADS  CAS  Google Scholar 

  20. Sun, R.; Ma, W.; Ling, M. J.; Tang, C. H.; Zhong, M.; Dai, J. Y.; Zhu, M. Y.; Cai, X. Z.; Li, G.; Xu, Q. et al. pH-activated nanoplatform for visualized photodynamic and ferroptosis synergistic therapy of tumors. J. Control. Release 2022, 350, 525–537.

    Article  PubMed  CAS  Google Scholar 

  21. Chen, X.; Tian, Z. Q.; Yang, Q. H.; Zhang, L. J.; Yang, Q.; Chen, L.; Lu, Z. Y. Cost- effective H2O2-regeneration of powdered activated carbon by isolated Fe sites. Adv. Sci. (Weinh.) 2023, 10, 2204079.

    PubMed  CAS  Google Scholar 

  22. Ji, S. F.; Jiang, B.; Hao, H. G.; Chen, Y. J.; Dong, J. C.; Mao, Y.; Zhang, Z. D.; Gao, R.; Chen, W. X.; Zhang, R. F. et al. Matching the kinetics of natural enzymes with a single-atom iron nanozyme. Nat. Catal. 2021, 4, 407–417.

    Article  CAS  Google Scholar 

  23. Wang, S. H.; Luo, J.; Zhang, Z. H.; Dong, D. D.; Shen, Y.; Fang, Y. W.; Hu, L. J.; Liu, M. Y.; Dai, C. F.; Peng, S. et al. Iron and magnetic: New research direction of the ferroptosis-based cancer therapy. Am. J. Cancer Res. 2018, 8, 1933–1946.

    PubMed  PubMed Central  CAS  Google Scholar 

  24. Liu, J. K.; Shen, W. L.; Zhao, B. L.; Wang, Y.; Wertz, K.; Weber, P.; Zhang, P. F. Targeting mitochondrial biogenesis for preventing and treating insulin resistance in diabetes and obesity: Hope from natural mitochondrial nutrients. Adv. Drug Deliv. Rev. 2009, 61, 1343–1352.

    Article  PubMed  CAS  Google Scholar 

  25. Botting, K. J.; Skeffington, K. L.; Niu, Y.; Allison, B. J.; Brain, K. L.; Itani, N.; Beck, C.; Logan, A.; Murray, A. J.; Murphy, M. P. et al. Translatable mitochondria-targeted protection against programmed cardiovascular dysfunction. Sci. Adv. 2020, 6, eabb1929.

    Article  ADS  PubMed  PubMed Central  CAS  Google Scholar 

  26. Zheng, Y. R.; Suntharalingam, K.; Johnstone, T. C.; Lippard, S. J. Encapsulation of Pt(IV) prodrugs within a Pt(II) cage for drug delivery. Chem. Sci. 2015, 6, 1189–1193.

    Article  PubMed  CAS  Google Scholar 

  27. Bulte, J. W. M.; Kraitchman, D. L. Iron oxide MR contrast agents for molecular and cellular imaging. NMR Biomed. 2004, 17, 484–499.

    Article  PubMed  CAS  Google Scholar 

  28. Garg, A. D.; Agostinis, P. Cell death and immunity in cancer: From danger signals to mimicry of pathogen defense responses. Immunol. Rev. 2017, 280, 126–148.

    Article  PubMed  CAS  Google Scholar 

  29. Krysko, D. V.; Garg, A. D.; Kaczmarek, A.; Krysko, O.; Agostinis, P.; Vandenabeele, P. Immunogenic cell death and DAMPs in cancer therapy. Nat. Rev. Cancer 2012, 12, 860–875.

    Article  PubMed  CAS  Google Scholar 

  30. Banchereau, J.; Steinman, R. M. Dendritic cells and the control of immunity. Nature 1998, 392, 245–252.

    Article  ADS  PubMed  CAS  Google Scholar 

  31. Byrne, A.; Savas, P.; Sant, S.; Li, R.; Virassamy, B.; Luen, S. J.; Beavis, P. A.; Mackay, L. K.; Neeson, P. J.; Loi, S. Tissue-resident memory T cells in breast cancer control and immunotherapy responses. Nat. Rev. Clin. Oncol. 2020, 17, 341–348.

    Article  PubMed  Google Scholar 

  32. Siegel, R. L.; Miller, K. D.; Jemal, A. Cancer statistics, 2019. CA Cancer J. Clin. 2019, 69, 7–34.

    Article  PubMed  Google Scholar 

  33. Li, S. D.; Ma, M.; Li, H.; Waluszko, A.; Sidorenko, T.; Schadt, E. E.; Zhang, D. Y.; Chen, R.; Ye, F. Cancer gene profiling in non-small cell lung cancers reveals activating mutations in JAK2 and JAK3 with therapeutic implications. Genome Med. 2017, 9, 89.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Son, J.; Lyssiotis, C. A.; Ying, H. Q.; Wang, X. X.; Hua, S. J.; Ligorio, M.; Perera, R. M.; Ferrone, C. R.; Mullarky, E.; Shyh-Chang, N. et al. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 2013, 496, 101–105.

    Article  ADS  PubMed  PubMed Central  CAS  Google Scholar 

  35. Moore, A. R.; Rosenberg, S. C.; McCormick, F.; Malek, S. Author correction: RAS-targeted therapies: Is the undruggable drugged? Nat. Rev. Drug Discov. 2020, 19, 902.

    Article  PubMed  CAS  Google Scholar 

  36. Davis, P. J.; Goglia, F.; Leonard, J. L. Nongenomic actions of thyroid hormone. Nat. Rev. Endocrinol. 2016, 12, 111–121.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The authors acknowledge the support from the National Natural Science Foundation of China (Nos. U21A20374, 82102903, and 52201285), Natural Science Foundation of Shanghai (No. 23ZR1479300), Shanghai Municipal Science and Technology Major Project (No. 21JC1401500), Scientific Innovation Project of Shanghai Education Committee (No. 2019-01-07-00-07-E00057), Zhejiang Provincial Natural Science Foundation (No. LQ22H160005), Zhejiang Medical Health Science and Technology Program (No. 2023RC031), and Ningbo Yongjiang Talent Introduction Program (No. 2021A-036-B).

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Author notes

  1. Haoqi Pan and Xu Chen contributed equally to this work.

Authors and Affiliations

  1. Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China

    Haoqi Pan, Mingming Xiao, He Xu & Xianjun Yu

  2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China

    Haoqi Pan, Mingming Xiao, He Xu & Xianjun Yu

  3. Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China

    Haoqi Pan & Si Shi

  4. Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China

    Haoqi Pan & Si Shi

  5. Key Laboratory of Advanced Fuel Cells and Electrolyzers Technology of Zhejiang Province, Qianwan Institute of CNITECH, Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo, 315201, China

    Xu Chen & Zhiyi Lu

  6. Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China

    Jiansheng Guo

  7. Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China

    Dong Cen

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  1. Haoqi Pan
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Correspondence to Dong Cen, Xianjun Yu or Si Shi.

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Multifunctional RGD coated a single-atom iron nanozyme: A highly selective approach to inducing ferroptosis and enhancing immunotherapy for pancreatic cancer

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Pan, H., Chen, X., Xiao, M. et al. Multifunctional RGD coated a single-atom iron nanozyme: A highly selective approach to inducing ferroptosis and enhancing immunotherapy for pancreatic cancer. Nano Res. (2024). https://doi.org/10.1007/s12274-024-6492-x

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  • DOI: https://doi.org/10.1007/s12274-024-6492-x

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