Citation: 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[J]. Chinese Chemical Letters, ;2026, 37(7): 111645. doi: 10.1016/j.cclet.2025.111645 shu

Ferrocene-integrated hypericin self-assembly nanocomplex directs ferroptosis for enhanced cascade tumor photodynamic therapy and immune effects

Xiaoxuan Zhou ^{a, 1} ,
Qiuhui Hu ^{a, 1} ,
Chengbin He ^a ,
Yue Qian ^a ,
Xiaodan Xu ^{b, *,} ,
Jianbin Tang ^{c, *,} ,
Hongjie Hu ^{a, *,}

a.
Department of Radiology, Sir Run Shaw Hospital (SRRSH) of School of Medicine, Zhejiang University, Hangzhou 310016, China
b.
Department of Ultrasound in Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China
c.
Key Laboratory of Smart Biomaterials of Zhejiang Province, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, China

xuxiaodan@zju.edu.cn

jianbin@zju.edu.cn

hongjiehu@zju.edu.cn

Received Date: 5 June 2025
Revised Date: 27 July 2025
Accepted Date: 29 July 2025
Available Online: 29 July 2025

Figures(6)

The antioxidant and immune-suppressive microenvironment of tumors has severely limited the efficacy of photodynamic therapy (PDT). To overcome these limitations, we proposed a novel nanoparticle (PEG-PFc/Hyp) that combined hypericin (Hyp) and ferrocene for synergistic anti-tumor therapy within a single system. Briefly, the optimum PEG₁₁₄-PLL₁₀ was reacted with ferrocene by the carboxylic acid N-succinimidyl ester(ferrocene-NHS), and the subsequent Hyp encapsulated in the above fabricated amphiphilic polymer. When under light irradiation, Hyp generated abundant reactive oxygen species (ROS) that synergized with ^•OH produced by ferrocene, leading to disrupted redox balance, amplified lethal lipid peroxidation (LPO) and inducing significant ferroptosis. Furthermore, the ferrocene could greatly alleviate hypoxia via O₂ production, thereby cascaded enhancing the ROS production efficiency of PDT. As a result, the cascade augmented ROS level, alongside the glutathione (GSH) depletion in tumor cells, caused effective immunogenic cell death (ICD) and potent anti-tumor response. It turned out that the PDT-ferroptosis-ICD strategy enabled significant oxidative damage and tumor cell immunogenicity, offering great potential in cancer immunotherapy.
- Fenton reaction,
- Hypericin,
- Photodynamic therapy,
- Ferroptosis,
- Immunogenic cell death
1. [1]
  J. Yates, E.M. Van Allen, Cancer Cell 43 (2025) 708–727. doi: 10.1016/j.ccell.2025.03.018
2. [2]
  D.J. Martini, C.J. Wu, Cancer Discov. 15 (2025) 1315–1324. doi: 10.1158/2159-8290.cd-25-0300
3. [3]
  S. Sen, M. Won, M.S. Levine, et al., Chem. Soc. Rev. 51 (2022) 1212–1233. doi: 10.1039/d1cs00417d
4. [4]
  S.W. Linderman, L. DeRidder, L. Sanjurjo, et al., Nat. Rev. Clin. Oncol. 22 (2025) 262–282. doi: 10.1038/s41571-025-01000-6
5. [5]
  Y. Pan, J. Cheng, Y. Zhu, et al., Chem. Soc. Rev. 53 (2024) 6399–6444. doi: 10.1039/d2cs00968d
6. [6]
  Z. Gao, X. Zheng, W. Liu, et al., Chin. Chem. Lett. 36 (2025) 109874. doi: 10.1016/j.cclet.2024.109874
7. [7]
  Q. Zhang, D. Chen, X. Liu, et al., Small 21 (2025) e2403165. doi: 10.1002/smll.202403165
8. [8]
  L. Jia, Y. Hong, X. He, et al., Chin. Chem. Lett. 36 (2025) 109957. doi: 10.1016/j.cclet.2024.109957
9. [9]
  X. Zhang, C. He, Y. Chen, et al., Biomaterials 275 (2021) 120987. doi: 10.1016/j.biomaterials.2021.120987
10. [10]
  H. Li, Y. Dou, H. Yang, et al., J. Nanobiotechnology 22 (2024) 100. doi: 10.1186/s12951-024-02346-2
11. [11]
  T. Yang, Q. Zhang, Y. Miao, et al., Adv. Mater. 37 (2024) e2403756.
12. [12]
  Y. Pei, Y. Pan, Z. Zhang, et al., Adv. Sci. 12 (2025) e2413879. doi: 10.1002/advs.202413879
13. [13]
  C. Liang, X. Liu, J. Yu, et al., J. Adv. Res. 77 (2025) 669–688. doi: 10.1016/j.jare.2025.01.042
14. [14]
  J. Fiegler-Rudol, N. Zięba, R. Turski, et al., Biomedicines 13 (2025) 181. doi: 10.3390/biomedicines13010181
15. [15]
  S. Li, J. E, X. Zhao, et al., Adv. Mater. 37 (2025) e2417198. doi: 10.1002/adma.202417198
16. [16]
  Y. Zhao, A. Linkermann, M. Takahashi, et al., Eur. Heart J. 46 (2025) 3247–3260. doi: 10.1093/eurheartj/ehaf374
17. [17]
  Y. Fan, Y. Wang, W. Dan, et al., Nat. Cell. Biol. 27 (2025) 641–653. doi: 10.1038/s41556-025-01610-3
18. [18]
  Y. Wang, C. Wu, C. Feng, et al., Chin. Chem. Lett. 36 (2025) 109902. doi: 10.1016/j.cclet.2024.109902
19. [19]
  L. Deng, M. Liu, D. Sheng, et al., Biomaterials 271 (2021) 120710. doi: 10.1016/j.biomaterials.2021.120710
20. [20]
  J. Wang, W. Zhang, Z. Xie, et al., Biomaterials 308 (2024) 122570. doi: 10.1016/j.biomaterials.2024.122570
21. [21]
  Q. Xiang, X. Yang, Z. Zhang, et al., Adv. Mater. 37 (2025) e2419120. doi: 10.1002/adma.202419120
22. [22]
  Y. Li, S. Han, Y. Zhao, et al., Small 21 (2024) e2404299.
23. [23]
  L. Shi, F. Hu, Y. Duan, et al., ACS Nano 14 (2020) 2183–2190. doi: 10.1021/acsnano.9b09032
24. [24]
  M.L. Patil, M. Zhang, T. Minko, ACS. Nano 5 (2011) 1877–1887. doi: 10.1021/nn102711d
25. [25]
  M. Souri, M. Soltani, F.Moradi Kashkooli, et al., Mater. Today Bio. 13 (2022) 100208.
26. [26]
  M.J. Mitchell, M.M. Billingsley, R.M. Haley, et al., Nat. Rev. Drug Discov. 20 (2021) 101–124. doi: 10.1038/s41573-020-0090-8
27. [27]
  Y. Li, B. Zhang, X. Liu, et al., J. Hazard Mater. 353 (2018) 26–34. doi: 10.1016/j.jhazmat.2018.02.034
28. [28]
  Y. Zhao, S. Zhang, Z. An, Angew. Chem. Int. Ed. 64 (2024) e202421851.
29. [29]
  A. Straube, L. Useini, E. Hey-Hawkins, Chem. Rev. 125 (2025) 3007–3058. doi: 10.1021/acs.chemrev.4c00295
30. [30]
  Z. Tang, P. Zhao, H. Wang, et al., Chem. Rev. 121 (2021) 1981–2019. doi: 10.1021/acs.chemrev.0c00977
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2. [2]
  Kun-Heng Li , Hong-Yang Zhao , Dan-Dan Wang , Ming-Hui Qi , Zi-Jian Xu , Jia-Mi Li , Zhi-Li Zhang , Shi-Wen Huang . Mitochondria-targeted nano-AIEgens as a powerful inducer for evoking immunogenic cell death. Chinese Chemical Letters, 2024, 35(5): 108882-. doi: 10.1016/j.cclet.2023.108882
3. [3]
  Yuequan Wang , Congtian Wu , Chengcheng Feng , Qin Chen , Zhonggui He , Shenwu Zhang , Cong Luo , Jin Sun . Spatiotemporally-controlled supramolecular hybrid nanoassembly enabling ferroptosis-augmented photodynamic immunotherapy of cancer. Chinese Chemical Letters, 2025, 36(3): 109902-. doi: 10.1016/j.cclet.2024.109902
4. [4]
  Liangliang Jia , Ye Hong , Xinyu He , Ying Zhou , Liujiao Ren , Hongjun Du , Bin Zhao , Bin Qin , Zhe Yang , Di Gao . Fighting hypoxia to improve photodynamic therapy-driven immunotherapy: Alleviating, exploiting and disregarding. Chinese Chemical Letters, 2025, 36(2): 109957-. doi: 10.1016/j.cclet.2024.109957
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  Qiuyue Lu , Min Shan , Jiaqi Yang , Zhongren Xu , Yueyue Lei , Wukun Liu . A dinuclear gold(I) complex with bis(N-heterocyclic carbene) ligands potentiated immune responses against liver cancer via ROS-driven endoplasmic reticulum stress and ferroptosis. Chinese Chemical Letters, 2025, 36(12): 110940-. doi: 10.1016/j.cclet.2025.110940
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  Shao-Qi Guan , Chen-Hui Liu , Ya-Ping Wang , Xiao-Dong Zhang , Zhong-Min Cao , Mei Pan . Cancer cell membrane-biomimetic metallacycles for tumor microenvironment-responsive ferroptosis/apoptosis therapy with low systemic toxicity. Chinese Chemical Letters, 2026, 37(7): 111692-. doi: 10.1016/j.cclet.2025.111692
7. [7]
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8. [8]
  Yongzhi Wu , Rong He , Bowen Tan , Longjiang Li , Jinfeng Liao . An injectable hydrogel for chemodynamic therapy-induced ferroptosis in malignant melanoma. Chinese Chemical Letters, 2026, 37(3): 111339-. doi: 10.1016/j.cclet.2025.111339
9. [9]
  Xinyue Lan , Junguang Liang , Churan Wen , Xiaolong Quan , Huimin Lin , Qinqin Xu , Peixian Chen , Guangyu Yao , Dan Zhou , Meng Yu . Photo-manipulated polyunsaturated fatty acid-doped liposomal hydrogel for flexible photoimmunotherapy. Chinese Chemical Letters, 2024, 35(4): 108616-. doi: 10.1016/j.cclet.2023.108616
10. [10]
  Lin Li , Bingjun Sun , Jin Sun , Lin Chen , Zhonggui He . Binary prodrug nanoassemblies combining chemotherapy and ferroptosis activation for efficient triple-negative breast cancer therapy. Chinese Chemical Letters, 2024, 35(10): 109538-. doi: 10.1016/j.cclet.2024.109538
11. [11]
  Zhendong Liu , Sainan Liu , Bin Liu , Qi Meng , Meng Yuan , Chunzheng Yang , Yulong Bian , Ping'an Ma , Jun Lin . Fe(Ⅲ)-juglone nanoscale coordination polymers for cascade chemodynamic therapy through synergistic ferroptosis and apoptosis strategy. Chinese Chemical Letters, 2024, 35(11): 109626-. doi: 10.1016/j.cclet.2024.109626
12. [12]
  Linping Zhao , Jianqiao Li , Guangmiao Chen , Chuyu Huang , Hangyu Zhou , Rongrong Zheng , Youqin Xu , Xueyan Jiang , Xiaohui Chen , Shiying Li . Cuproptosis amplifier of copper-telaglenastat coordinate to trigger cell ferroptosis for synergistic breast cancer suppression. Chinese Chemical Letters, 2026, 37(1): 110959-. doi: 10.1016/j.cclet.2025.110959
13. [13]
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14. [14]
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15. [15]
  Jiao Lu , Bin Yang , Zhou Wu , Yong Li , Jun Wang , Ruihong Yao , Yanli Li , Zhihao Lu , Yufei Jiang , Fabiao Yu , Zhirong Geng , Zhilin Wang . Dual-activated fluorescent sensor visualizes energy metabolism pathways under ferroptosis-mediated oxidative stress relevant to cancer therapy. Chinese Chemical Letters, 2026, 37(5): 111334-. doi: 10.1016/j.cclet.2025.111334
16. [16]
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17. [17]
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18. [18]
  Jia-Yin Su , Shiyao Song , Zi-Min Song , Xi Sun , Niangji Tsomo , Ying-Li Liu , Jingxuan Ma , Jie-Si Luo , Li-Na Wang , Suoyu Xiang , Cong Liang , Xue-Qun Luo , Jun Wu , Li-Bin Huang , Yan-Lai Tang . Arsenic trioxide-induced pyroptosis promotes the release of HMGB1 to activate natural killer cells related immunogenic cell death in leukemia. Chinese Chemical Letters, 2026, 37(7): 111585-. doi: 10.1016/j.cclet.2025.111585
19. [19]
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