Citation: Yupeng Wang, Xinxin Sun, Jianbin Shi, Zhixiao Zhang, Jin Sun, Cong Luo, Zhonggui He, Shenwu Zhang. Chain architecture-engineered artesunate nanoassemblies target LONP1 to induce oxidative damage for enhanced anti-tumor therapy[J]. Chinese Chemical Letters, ;2026, 37(1): 111609. doi: 10.1016/j.cclet.2025.111609 shu

Chain architecture-engineered artesunate nanoassemblies target LONP1 to induce oxidative damage for enhanced anti-tumor therapy

Yupeng Wang ^{a, 1} ,
Xinxin Sun ^{a, 1} ,
Jianbin Shi ^a ,
Zhixiao Zhang ^c ,
Jin Sun ^{a, b} ,
Cong Luo ^{a, b} ,
Zhonggui He ^{a, b, *,} ,
Shenwu Zhang ^{a, *,}

a.
Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China
b.
Joint International Research Laboratory of Intelligent Drug Delivery Systems of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
c.
Department of Pharmacy, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121000, China

hezhonggui@vip.163.com

zhangshenwu@aliyun.com

Received Date: 26 March 2025
Revised Date: 16 July 2025
Accepted Date: 18 July 2025
Available Online: 18 July 2025

Figures(4)

Despite demonstrating significant anti-tumor potential as an artemisinin derivative, artesunate faces delivery efficiency challenges due to low water solubility and insufficient targeting specificity. To improve the delivery efficiency, we engineered three artesunate (ART) derivatives, AC₁₅-L (linear), AC₁₅-B (branched), and AC₁₅-C (cyclic) with distinct aliphatic chain architectures. Unexpectedly, we observed that AC₁₅-C exhibited superior cytotoxicity against 4T1 breast cancer cells, and had the highest binding affinity for Lon protease 1 (LONP1) (−72.6 kcal/mol). Subsequently, disulfide bond-containing lipid-PEG (DSPE-SS-PEG_2K) modified chain architecture-engineered ART derivatives nanoassemblies (NAs) were developed to mitigate solubility-related limitations while enhancing targeting precision. Molecular docking and experimental validation demonstrated that ART derivatives inhibited LONP1 through hydrophobic interactions while preserved Fe²⁺-mediated Fenton-like reaction activity. In vitro and in vivo evaluations demonstrated that AC₁₅-C NAs outperformed free ART and other NAs, suppressing 4T1 tumor growth via dual action: LONP1-directed mitochondrial proteostasis collapse and reactive oxygen species (ROS) amplification through Fe²⁺-ART interactions. This study elucidated a novel anti-tumor mechanism of ART through the rational design of derivatives with spatially configured aliphatic chains, and developed reduction-responsive NAs to provide an advanced delivery strategy.
- Chain architecture engineering,
- ART,
- LONP1,
- Nanoassemblies,
- Cancer therapy
1. [1]
  Nat. Cancer 1 (2020) 1–2.
2. [2]
  F. Bray, M. Laversanne, H. Sung, et al., CA Cancer J. Clin. 74 (2024) 229–263.
3. [3]
  U. Anand, A. Dey, A.K.S. Chandel, et al., Genes Dis. 10 (2023) 1367–1401. doi: 10.1016/j.gendis.2022.02.007
4. [4]
  D. Li, Y. Wang, C. Li, et al., Acta Pharm. Sin. B 11 (2021) 3262–3271. doi: 10.1016/j.apsb.2021.04.009
5. [5]
  M.D. Hellmann, B.T. Li, J.E. Chaft, et al., Ann. Oncol. 27 (2016) 1829–1835. doi: 10.1093/annonc/mdw271
6. [6]
  R.A. Smith, K.S. Andrews, D. Brooks, et al., CA Cancer J. Clin. 69 (2019) 184–210.
7. [7]
  T. Das, U. Anand, S.K. Pandey, et al., Drug Resist. Updat. 55 (2021) 100754. doi: 10.1016/j.drup.2021.100754
8. [8]
  E.B. Garon, T.E. Ciuleanu, O. Arrieta, et al., Lancet 384 (2014) 665–673. doi: 10.1016/S0140-6736(14)60845-X
9. [9]
  L. Tong, C.C. Chuang, S. Wu, et al., Cancer Lett. 367 (2015) 18–25. doi: 10.1016/j.canlet.2015.07.008
10. [10]
  D. Hu, Y. Li, R. Li, et al., Acta Pharm. Sin. B 14 (2024) 5106–5131. doi: 10.1016/j.apsb.2024.10.015
11. [11]
  P. Wang, Q. Gong, J. Hu, et al., J. Med. Chem. 64 (2021) 298–325. doi: 10.1021/acs.jmedchem.0c01704
12. [12]
  E.C. Cheung, et al., Nat. Rev. Cancer 22 (2022) 280–297. doi: 10.1038/s41568-021-00435-0
13. [13]
  J. Wang, C. Xu, Y.K. Wong, et al., Engineering 5 (2019) 32–39. doi: 10.1016/j.eng.2018.11.011
14. [14]
  F. Sun, Y. Peng, Y. Li, et al., Chin. Chem. Lett. 34 (2023) 107507. doi: 10.1016/j.cclet.2022.05.021
15. [15]
  Y.D. Zhao, Y. Wang, R. Wang, et al., Chin. Chem. Lett. 35 (2024) 108929. doi: 10.1016/j.cclet.2023.108929
16. [16]
  C. Xu, H. Zhang, L. Mu, et al., Front. Pharmacol. 11 (2020) 529881. doi: 10.3389/fphar.2020.529881
17. [17]
  Y.G. Lee, H.W. Kim, Y. Nam, et al., Oncogenesis 10 (2021) 18. doi: 10.1038/s41389-021-00306-1
18. [18]
  Y. Matsushima, Mitochondrial AAA+ proteases, in: F. Tamanoi (Ed.), The Enzymes: AAA+ Proteases and ATP-dependent Proteolysis, 54, 1st ed., Academic Press (Elsevier), Cambridge, MA, 2023, pp. 205–220.
19. [19]
  Q. Zhang, W. Chen, B. Zhang, et al., Food Chem. Toxicol. 172 (2023) 113592. doi: 10.1016/j.fct.2022.113592
20. [20]
  Y. Liu, J. Jiang, S. Du, et al., Science 384 (2024) eadk5382. doi: 10.1126/science.adk5382
21. [21]
  Z. Zhao, F. Yang, X. Zhang, et al., Biomaterials 255 (2020) 120200. doi: 10.1016/j.biomaterials.2020.120200
22. [22]
  F. Yang, Z. Zhao, B. Sun, et al., Trends Cancer 6 (2020) 645–659. doi: 10.1016/j.trecan.2020.05.001
23. [23]
  C. Luo, J. Sun, B. Sun, et al., Trends Pharmacol. Sci. 35 (2014) 556–566. doi: 10.1016/j.tips.2014.09.008
24. [24]
  J. Zuo, X. Gao, J. Xiao, et al., Chin. Chem. Lett. 34 (2023) 107827. doi: 10.1016/j.cclet.2022.107827
25. [25]
  R. Liu, C. Luo, Z. Pang, et al., Chin. Chem. Lett. 34 (2023) 107518. doi: 10.1016/j.cclet.2022.05.032
26. [26]
  C. Wang, H. Yu, X. Yang, et al., Asian J. Pharm. Sci. 17 (2022) 412–424.
27. [27]
  X. Zhang, N. Li, S. Zhang, et al., Med. Res. Rev. 40 (2020) 1754–1775. doi: 10.1002/med.21669
28. [28]
  Y. Chen, X. Shan, C. Luo, et al., J. Pharm. Investig. 50 (2020) 219–230. doi: 10.1007/s40005-020-00480-1
29. [29]
  Y. Chen, T. Zhao, M. Bai, et al., Chem. Eng. J. 435 (2022) 135160. doi: 10.1016/j.cej.2022.135160
30. [30]
  S. Zhang, Z. Wang, Z. Kong, et al., Theranostics 11 (2021) 6019–6032. doi: 10.7150/thno.59065
31. [31]
  S. Zhang, Y. Wang, Z. Kong, et al., Acta Pharm. Sin. B 11 (2021) 3636–3647. doi: 10.1016/j.apsb.2021.04.005
32. [32]
  B. Sun, C. Luo, X. Zhang, et al., Nat. Commun. 10 (2019) 3211. doi: 10.1038/s41467-019-11193-x
33. [33]
  C. Luo, J. Sun, B. Sun, et al., Small 12 (2016) 6353–6362. doi: 10.1002/smll.201601597
34. [34]
  S. Mollazadeh, et al., Mater. Sci. Eng. C 118 (2021) 111536. doi: 10.1016/j.msec.2020.111536
35. [35]
  S.S. Das, P. Bharadwaj, M. Bilal, et al., Imaging Ther. Polym. 12 (2020) 1397.
36. [36]
  Y. Yang, W. Zeng, P. Huang, et al., VIEW 2 (2021) 20200042. doi: 10.1002/VIW.20200042
37. [37]
  Y. Yang, S. Zuo, J. Zhang, et al., Nano Today 44 (2022) 101480. doi: 10.1016/j.nantod.2022.101480
38. [38]
  X. Fan, Y. Yan, Y. Li, et al., Front. Pharmacol. 15 (2024) 1483049. doi: 10.3389/fphar.2024.1483049
39. [39]
  S. Shan, Z. Liu, S. Wang, et al., Ecotoxicol. Environ. Saf. 264 (2023) 115409. doi: 10.1016/j.ecoenv.2023.115409
1. [1]
  Menglin Zhang , Fanpeng Ran , Yun Zhang , Xiaoli Zhang , Zhigang Xu , Xiaoxiao Shi . Cyclodextrin-based nanotherapeutics: A promising strategy for enhanced cancer therapy. Chinese Chemical Letters, 2026, 37(1): 111232-. doi: 10.1016/j.cclet.2025.111232
2. [2]
  Zhaoyong Kang , Shen Li , Yan Li , Jingfeng Song , Yangrui Peng , Yihua Chen . Small molecular inhibitors and degraders targeting STAT3 for cancer therapy: An updated review (from 2022 to 2024). Chinese Chemical Letters, 2025, 36(7): 110447-. doi: 10.1016/j.cclet.2024.110447
3. [3]
  Hao Hu , Jiacheng Wang , Si Zhang , Ben Zhang , Cuinan Jiang , Hong Tian , Xunxin Gu , Yang Sheng , Zhenghuan Zhao , Meng Li , Lu Zheng , Jing Li . Hierarchical and flexible electrode with precise H₂-production for in vivo liver cancer therapy. Chinese Chemical Letters, 2025, 36(12): 110866-. doi: 10.1016/j.cclet.2025.110866
4. [4]
  Shengyi Gong , Guoqiang Feng . Visible light-triggered NIR ratiometric fluorescent metal-free CO-releasing molecule for self-monitoring of CO delivery and effective cancer therapy. Chinese Chemical Letters, 2025, 36(7): 110409-. doi: 10.1016/j.cclet.2024.110409
5. [5]
  Xin Li , Fei Xiong , Xudong Cao , Wei Liu , Haobo Chen , Jiayu He , Weina Zhang , Longguang Tang , Wei Huang , Xikuang Yao . CD44-targeting and ZIF-8 gated gold nanocage for programmed breast cancer therapy through Pt-induced immunogenic cell death. Chinese Chemical Letters, 2026, 37(1): 110970-. doi: 10.1016/j.cclet.2025.110970
6. [6]
  Yuanyi Zhou , Ke Ma , Jinfeng Liu , Zirun Zheng , Bo Hu , Yu Meng , Zhizhong Li , Mingshan Zhu . Is reactive oxygen species the only way for cancer inhibition over single atom nanomedicine? Autophagy regulation also works. Chinese Chemical Letters, 2024, 35(6): 109056-. doi: 10.1016/j.cclet.2023.109056
7. [7]
  Linzhou Yin , Xiaowen Jiang , Miao Wang , Yiren Yang , Zhonggui He , Jin Sun , Huiyuan Gao , Mengchi Sun . Phytoconstituent-derived nano-medicines/vesicles providing a promising dawn for inflammatory bowel disease. Chinese Chemical Letters, 2025, 36(6): 110224-. doi: 10.1016/j.cclet.2024.110224
8. [8]
  Ziqin Li , Kai Hao , Longwei Xiang , Huayu Tian . Cationic covalent organic framework nanocarriers integrating both efficient gene silencing and real-time gene detection. Chinese Chemical Letters, 2025, 36(4): 109943-. doi: 10.1016/j.cclet.2024.109943
9. [9]
  Yixin Sun , Keke Yu , Xiuchun Guo , Lanlan Zong , Zhonggui He , Xiaohui Pu . Three-in-one reduction and acid-ignited micelles amplify antitumor efficacy via precise synergistic delivery of paclitaxel and naringenin. Chinese Chemical Letters, 2025, 36(6): 110393-. doi: 10.1016/j.cclet.2024.110393
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]
  Yunyan Li , Zimin Cai , Zhicheng Wang , Sifeng Zhu , Wendian Liu , Cheng Wang . Construction of biomimetic hybrid nanovesicles based on M1 macrophage-derived exosomes for therapy of cancer. Chinese Chemical Letters, 2025, 36(4): 109942-. doi: 10.1016/j.cclet.2024.109942
12. [12]
  Yuqing Zhu , Haohao Chen , Li Wang , Liqun Ye , Houle Zhou , Qintian Peng , Huaiyong Zhu , Yingping Huang . Piezoelectric materials for pollutants degradation: State-of-the-art accomplishments and prospects. Chinese Chemical Letters, 2024, 35(4): 108884-. doi: 10.1016/j.cclet.2023.108884
13. [13]
  Yanghanbin Zhang , Dongxiao Wen , Wei Sun , Jiahe Peng , Dezhong Yu , Xin Li , Yang Qu , Jizhou Jiang . State-of-the-art evolution of g-C3N4-based photocatalytic applications: A critical review. Chinese Journal of Structural Chemistry, 2024, 43(12): 100469-100469. doi: 10.1016/j.cjsc.2024.100469
14. [14]
  Hong-Yu Chu , Guang-Chi Liu , Fu-Xue Wang , Lian-Sheng Cui , Chong-Chen Wang . Microcystis aeruginosa removal over MOFs-based materials and the evaluation methods: State-of-the-art review. Chinese Chemical Letters, 2025, 36(10): 110745-. doi: 10.1016/j.cclet.2024.110745
15. [15]
  Qihang Wu , Hui Wen , Wenhai Lin , Tingting Sun , Zhigang Xie . Alkyl chain engineering of boron dipyrromethenes for efficient photodynamic antibacterial treatment. Chinese Chemical Letters, 2024, 35(12): 109692-. doi: 10.1016/j.cclet.2024.109692
16. [16]
  Huijie An , Chen Yang , Zhihui Jiang , Junjie Yuan , Zhongming Qiu , Longhao Chen , Xin Chen , Mutu Huang , Linlang Huang , Hongju Lin , Biao Cheng , Hongjiang Liu , Zhiqiang Yu . Luminescence-activated Pt(Ⅳ) prodrug for in situ triggerable cancer therapy. Chinese Chemical Letters, 2024, 35(7): 109134-. doi: 10.1016/j.cclet.2023.109134
17. [17]
  Mengjuan Sun , Muye Zhou , Yifang Xiao , Hailei Tang , Jinhua Chen , Ruitao Zhang , Chunjiayu Li , Qi Ya , Qian Chen , Jiasheng Tu , Qiyue Wang , Chunmeng Sun . Reversibly size-switchable polyion complex micelles for antiangiogenic cancer therapy. Chinese Chemical Letters, 2024, 35(7): 109110-. doi: 10.1016/j.cclet.2023.109110
18. [18]
  Xiaofang Luo , Ye Wu , Xiaokun Zhang , Min Tang , Feiye Ju , Zuodong Qin , Gregory J Duns , Wei-Dong Zhang , Jiang-Jiang Qin , Xin Luan . Peptide-based strategies for overcoming multidrug-resistance in cancer therapy. Chinese Chemical Letters, 2025, 36(1): 109724-. doi: 10.1016/j.cclet.2024.109724
19. [19]
  Lijuan Liu , Zhihao Zhao , Feiwan Zou , Wukun Liu , Yunlong Lu . Advances in combination therapy for the treatment of estrogen receptor positive breast cancer. Chinese Chemical Letters, 2025, 36(10): 111451-. doi: 10.1016/j.cclet.2025.111451
20. [20]
  Jin-Ao Li , Nana Pan , Li Lu , Yifan Wei , Wenchang Hu , Zhiyang Zhang , Houda Amrani , Fang Huang , Xiaojuan Wang . Ligand-bridged nanoassemblies boost the peroxidase-mimicking activity of gold nanoclusters. Chinese Chemical Letters, 2026, 37(1): 111806-. doi: 10.1016/j.cclet.2025.111806

Get Citation

PDF

XML

Metrics

PDF Downloads(0)
Abstract views(5)
HTML views(1)

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142