Citation: Xuan Wu, Ming Liu, Xiao Wang, Jie Niu, Ting-Long Zhuang, Xiaohuan Sun, Liqi Zhu, Quan Zhang, Jie Han, Rong Guo. pH-mediated selective self-assembly in the mitochondria of cancer cells for synergetic ferroptosis[J]. Chinese Chemical Letters, ;2026, 37(9): 112198. doi: 10.1016/j.cclet.2025.112198 shu

pH-mediated selective self-assembly in the mitochondria of cancer cells for synergetic ferroptosis

Xuan Wu ^{a, *,} ,
Ming Liu ^b ,
Xiao Wang ^a ,
Jie Niu ^c ,
Ting-Long Zhuang ^d ,
Xiaohuan Sun ^a ,
Liqi Zhu ^d ,
Quan Zhang ^{d, *,} ,
Jie Han ^{a, *,} ,
Rong Guo ^a

a.
School of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou 225002, China
b.
The Forth People Hospital of Changsha: Changsha Hospital of Hunan Normal University, Changsha 410000, China
c.
Medical College, Institute of Translational Medicine, Yangzhou University, Yangzhou 225009, China
d.
College of Veterinary Medicine, Yangzhou University, Yangzhou 225002, China

wuxuan@wibe.ac.cn

zquan@yzu.edu.cn

hanjie@yzu.edu.cn

Received Date: 28 July 2025
Revised Date: 20 November 2025
Accepted Date: 28 November 2025
Available Online: 29 November 2025

Figures(8)

Selective targeting to the subcellular organelle of cancer cells could provide a novel method to realize precise in situ self-assembly for enhanced therapeutic efficiency. Herein, a series of cationic compounds have been synthesized to investigate their subcellular targeting abilities, we found the amino group functionalized planar cationic molecules could selectively locate in the mitochondria of cancer cells (Pearson's coefficient > 0.9), while in the lysosomes of normal cells (Pearson's coefficient > 0.9). Moreover, due to the intermolecular hydrogen bond, the TPE derivative (TPE-NH₂) was selected to investigate the in situ self-assembly behavior with negatively charged molecules in the mitochondria of MB49 cancer cells, which could impair the mitochondrial membrane, leading to the elevated reactive oxygen species (ROS), downregulating glutathione peroxidase 4 (GPX4) protein, and finally resulting in LPO for ferroptosis. Moreover, the aggregation-enhanced ROS generation ability of TPE-NH₂ made it an ideal candidate for PDT. Under the white light irradiation, the synergetic ferroptosis could be realized to suppress the cancer cell proliferation. Finally, this in situ self-assembly for synergetic therapy would also be realized in vivo to suppress the tumor growth.
- Supramolecular self-assembly,
- Subcellular targeting,
- In situ self-assembly,
- Mitochondrial dysfunction,
- Synergetic therapy,
- Ferroptosis
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