Citation: Ying Chen, Jun Zhang, Haoran Ye, Shengli Shen, Junyu Wang, Juan Wang, Xintong Li, Xinghong Luo, Ling Tao, Wenchuang (Walter) Hu, Xiangchun Shen, Yongchao Yao. Spatial-isolated oil-water biphasic Pickering emulsions inhibit premature disulfiram-copper interaction for enhanced chemo-cuproptosis synergy[J]. Chinese Chemical Letters, ;2026, 37(11): 112187. doi: 10.1016/j.cclet.2025.112187 shu

Spatial-isolated oil-water biphasic Pickering emulsions inhibit premature disulfiram-copper interaction for enhanced chemo-cuproptosis synergy

Ying Chen ^{a, b, 1} ,
Jun Zhang ^{a, b, 1} ,
Haoran Ye ^{a, b, 1} ,
Shengli Shen ^{a, b} ,
Junyu Wang ^{a, b} ,
Juan Wang ^{a, b} ,
Xintong Li ^{a, b} ,
Xinghong Luo ^{a, b} ,
Ling Tao ^{a, b, *,} ,
Wenchuang (Walter) Hu ^{c, *,} ,
Xiangchun Shen ^{a, b, *,} ,
Yongchao Yao ^{c, *,}

a.
State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine & School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 561113, China
b.
Guizhou International Science & Technology Cooperation Base for Druggability Research of Natural Medicines & The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province, Guizhou Medical University, Guiyang 561113, China
c.
Precision Medicine Translational Research Center (PMTRC), West China Hospital, Sichuan University, Chengdu 610041, China

taoling@gmc.edu.cn

huwenchuang@wchscu.cn

shenxiangchun@126.com

hatuu@wchscu.edu.cn

Received Date: 16 October 2025
Revised Date: 25 November 2025
Accepted Date: 26 November 2025
Available Online: 27 November 2025

Figures(6)

Disulfiram/copper (DSF/Cu) co-delivery systems exhibit significant potential for tumor-specific chemotherapy. However, their efficacy is severely limited by premature interaction between DSF and Cu, which triggers off-target generation of cytotoxic copper−diethyldithiocarbamate complexes (CuET) and degradation. Herein, we develop a spatial-isolated oil-water biphasic Pickering emulsion (DBCP) stabilized by bovine serum albumin-copper nanoclusters (BSA-CuNCs), designed to inhibit such premature interaction through phase-separated co-delivery. Specifically, lipophilic DSF is encapsulated in the oil phase, while hydrophilic Cu²⁺ is chelated in the BSA-based emulsifier layer at the oil-water interface, achieving strict spatial segregation to block their untimely reaction. Endowed with enhanced permeability and retention (EPR) effect and BSA-mediated active targeting, DBCP accumulates specifically in tumor tissues. Upon cellular uptake, pH/glutathione dual stimulation triggers synchronous release of DSF and Cu, which then generate cytotoxic CuET in situ, catalyze Fenton-like reaction for chemotherapy, and induce cuproptosis via mitochondrial copper accumulation and dihydrolipoamide S-acetyltransferase (DLAT) binding, finally realizing enhanced chemo-cuproptosis synergy. In vitro, DBCP exhibits an median inhibition concentration (IC₅₀) as low as 0.60 µmol/L against 4T1 cells, markedly enhancing DSF's antitumor activity. In vivo, it achieves a 74.41% tumor inhibition rate in 4T1-bearing mice (vs. 52.67% for 5-Fu) with negligible toxicity. This spatial-isolated oil-water biphasic Pickering emulsion offers a novel strategy to harness the therapeutic potential of DSF/Cu for clinical translation.
- Pickering emulsion,
- Spatial-isolated,
- Disulfiram-copper,
- Chemotherapy,
- Cuproptosis
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