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
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