Citation: Yirou Wang, Futing Yang, Jun Wang, Xinghua Liao, Chun Song, Michał Nowicki, Roman Szewczyk, Na Peng. Glutathione-activated mitochondria-targeting nanosystem overcoming ferroptosis defence for dual synergism with apoptosis to enhance anti-tumor efficacy of sonodynamic therapy[J]. Chinese Chemical Letters, ;2026, 37(8): 111771. doi: 10.1016/j.cclet.2025.111771 shu

Glutathione-activated mitochondria-targeting nanosystem overcoming ferroptosis defence for dual synergism with apoptosis to enhance anti-tumor efficacy of sonodynamic therapy

Yirou Wang ^{a, 1} ,
Futing Yang ^{a, 1} ,
Jun Wang ^{a, 1} ,
Xinghua Liao ^{a, 1} ,
Chun Song ^a ,
Michał Nowicki ^c ,
Roman Szewczyk ^c ,
Na Peng ^{a, b, *,}

a.
Key Laboratory of Coal Conversion and New Carbon Materials of Hubei Province, School of Chemistry and Chemical Engineering, College of Life and Health Sciences, Wuhan University of Science and Technology, Wuhan 430081, China
b.
Chia-Poland Belt and Road Joint Laboratory on Measurement and Control Technology, Huazhong University of Science and Technology, Wuhan 430074, China
c.
Institute of Metrology and Biomedical Engineering Faculty of Mechatronics, Warsaw University of Technology, Warsaw 00-661, Poland

pengna@wust.edu.cn

Received Date: 14 May 2025
Revised Date: 25 August 2025
Accepted Date: 28 August 2025
Available Online: 28 August 2025

Figures(5)

Triggering mitochondria-targeted ferroptosis is the effective way to bypass apoptotic resistance of sonodynamic therapy (SDT), but it suffers from discounted therapeutic efficacy due to the anti-ferroptosis mechanism via mitochondrial dihydroorotate dehydrogenase (DHODH). Herein, iron porphyrin-based nanometal organic frameworks (PCN-600) were synthesized by hydrothermal method for loading the ferroptosis inducer sulfasalazine (SAS) and DHODH inhibitor brequinar (BQR), and finally surface-modified with short chains of mitochondria-targeting triphenylphosphine (TPP) and long chains contained tumor-targeting groups of biotin that can be cleaved by intratumoral glutathione (GSH) to re-expose TPP. The nanosystem could be successfully delivered into the mitochondria of cancer cells which was an important location of cell apoptosis and ferroptosis, released SAS/BQR, and produced amounts of ROS under ultrasound activation to induce ferroptosis and overcome ferroptosis resistance for dual-synergism with apoptosis to enhance the anti-tumor efficacy of SDT both in vitro and in vivo. The GSH-activated mitochondria-targeting nanosystem for devasting mitochondrial anti-ferroptosis provides a novel method for ferroptosis-based enhancement of anti-tumor efficacy of SDT.
- Mitochondria-targeted,
- Apoptosis,
- Ferroptosis,
- Dihydroorotate dehydrogenase,
- Sonodynamic therapy
1. [1]
  H. Sung, J. Ferlay, R.L. Siegel, et al., CA Cancer J. Clin. 71 (2021) 209–249. doi: 10.3322/caac.21660
2. [2]
  L. Wang, C. Lynch, S. Pitroda, et al., J. Exp. Med. 221 (2024) e20232101. doi: 10.1084/jem.20232101
3. [3]
  M. Singh, V.K. Morris, I.N. Bandey, et al., Trends Cancer 10 (2024) 598–609. doi: 10.1016/j.trecan.2024.05.001
4. [4]
  M. Ling, R. Sun, W. Ma, et al., Nano Res. 15 (2022) 6288–6296. doi: 10.1007/s12274-022-4239-0
5. [5]
  K. Song, G. Chen, Z. He, et al., Acta Biomater. 158 (2023) 637–648. doi: 10.1016/j.actbio.2022.12.065
6. [6]
  Z. Xiao, Q. Chen, Y. Yang, et al., Chem. Eng. J. 449 (2022) 137889. doi: 10.1016/j.cej.2022.137889
7. [7]
  H. Xu, N. Yu, J. Zhang, et al., Biomaterials 257 (2020) 120239. doi: 10.1016/j.biomaterials.2020.120239
8. [8]
  M. Yuan, S. Liang, Y. Zhou, et al., Nano Lett. 21 (2021) 6042–6050. doi: 10.1021/acs.nanolett.1c01220
9. [9]
  X. Deng, Z. Shao, Y. Zhao, Adv. Sci. 8 (2021) 2002504. doi: 10.1002/advs.202002504
10. [10]
  Z. Zhu, Y. Liu, C. Song, et al., ACS Nano 16 (2021) 1346–1357. doi: 10.1007/s11427-020-1842-7
11. [11]
  Y. Cao, S. Zhang, Z. Lv, et al., Adv. Funct. Mater. 32 (2022) 2209227. doi: 10.1002/adfm.202209227
12. [12]
  L. Zhou, C. Dong, L. Ding, et al., Nano Today 39 (2021) 101212. doi: 10.1016/j.nantod.2021.101212
13. [13]
  M. Zhan, F. Wang, Y. Liu, et al., Adv. Sci. 10 (2023) e2207200. doi: 10.1002/advs.202207200
14. [14]
  Q. Wang, F. Shaik, X. Lu, et al., Acta Biomater. 155 (2023) 575–587. doi: 10.1016/j.actbio.2022.10.048
15. [15]
  Y. Li, Y. Duan, Y. Li, et al., Exploration 5 (2024) 20230117.
16. [16]
  B. Hassannia, P. Vandenabeele, T.V. Berghe, Cancer Cell 35 (2019) 830–849. doi: 10.1016/j.ccell.2019.04.002
17. [17]
  F. Cao, Y. Sang, C. Liu, et al., ACS Nano 16 (2022) 855–868. doi: 10.1021/acsnano.1c08464
18. [18]
  H. Yu, J. Yan, Z. Li, et al., Nanoscale Adv. 5 (2023) 1271–1290. doi: 10.1039/d2na00719c
19. [19]
  X. Bai, J. Kang, S. Wei, et al., Exploration 5 (2024) 20240002.
20. [20]
  N. Montesdeoca, L. Johannknecht, E. Efanova, et al., Angew. Chem. Int. Ed. 63 (2024) e202412585. doi: 10.1002/anie.202412585
21. [21]
  Q. Jiang, K. Wang, X. Zhang, et al., Small 16 (2020) 2001704. doi: 10.1002/smll.202001704
22. [22]
  E. Mishima, T. Nakamura, J. Zheng, et al., Nature 619 (2023) 9–18. doi: 10.1038/d41586-023-02208-1
23. [23]
  C. Mao, X. Liu, Y. Zhang, et al., Nature 593 (2021) 586–590. doi: 10.1038/s41586-021-03539-7
24. [24]
  P. Xue, H. Zhuang, S. Shao, et al., ACS Nano 18 (2024) 25795–25812. doi: 10.1021/acsnano.4c08574
25. [25]
  C. Yin, Y. Li, Z. Liao, et al., Acta Biomater. 155 (2023) 491–506. doi: 10.1016/j.actbio.2022.11.037
26. [26]
  X. Han, Z. Song, Y. Zhou, et al., Biomater. Adv. 124 (2021) 112054.
27. [27]
  F. Qu, P. Wang, K. Zhang, et al., Autophagy 16 (2020) 1413–1435. doi: 10.1080/15548627.2019.1687210
28. [28]
  B. Kalyanaraman, G. Cheng, M. Hardy, et al., Interface Focus 7 (2017) 20160109. doi: 10.1098/rsfs.2016.0109
29. [29]
  L. Zhang, Y. Jia, H. Hao, et al., Micropor. Mesopor. Mater. 344 (2022) 112198. doi: 10.1016/j.micromeso.2022.112198
30. [30]
  S. Zhang, Q. Fu, Y. Zhang, et al., Acta Pharmacol. Sin. 42 (2021) 1040–1054. doi: 10.1038/s41401-020-00606-z
31. [31]
  Y. Feng, G. Qin, S. Chang, et al., Int. J. Nanomed. 16 (2021) 3073–3089. doi: 10.2147/ijn.s297716
32. [32]
  M. He, Z. Zhang, Z. Jiao, et al., Chin. Chem. Lett. 34 (2023) 107574. doi: 10.1016/j.cclet.2022.05.088
33. [33]
  F. Yang, W. Yu, Q. Yu, et al., Small 19 (2023) e2206124. doi: 10.1002/smll.202206124
34. [34]
  J. Wang, Y. Fan, Y. Tan, et al., ACS Appl. Mater. Interfaces 10 (2018) 36615–36621. doi: 10.1021/acsami.8b15452
35. [35]
  Z.S. Moghaddam, M. Kaykhaii, M. Khajeh, et al., Anal. Methods 12 (2020) 651–656. doi: 10.1039/C9AY01769K
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  Xiaoxuan Zhou , Qiuhui Hu , Chengbin He , Yue Qian , Xiaodan Xu , Jianbin Tang , Hongjie Hu . Ferrocene-integrated hypericin self-assembly nanocomplex directs ferroptosis for enhanced cascade tumor photodynamic therapy and immune effects. Chinese Chemical Letters, 2026, 37(7): 111645-. doi: 10.1016/j.cclet.2025.111645
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  Li Qin , Wenjing Wei , Keqing Wang , Xianbao Shi , Guixia Ling , Peng Zhang . Ultrasound-responsive heterojunction sonosensitizers for multifunctional synergistic sonodynamic therapy. Chinese Chemical Letters, 2025, 36(7): 110777-. doi: 10.1016/j.cclet.2024.110777
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