Degradation of dual proteins induced by “power train”

Rui Liang; Kunhan Nie; Beibei Lou; Lin Liu; Xiaoqiao Wu; Chun Tian; Hui Liu; Chengzhi Huang; Di Li; Chunmei Li

doi:10.1016/j.jpha.2026.101639

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Rui Liang, Kunhan Nie, Beibei Lou, Lin Liu, Xiaoqiao Wu, Chun Tian, Hui Liu, Chengzhi Huang, Di Li, Chunmei Li. Degradation of dual proteins induced by “power train”[J]. Journal of Pharmaceutical Analysis. doi: 10.1016/j.jpha.2026.101639

Citation:

Rui Liang, Kunhan Nie, Beibei Lou, Lin Liu, Xiaoqiao Wu, Chun Tian, Hui Liu, Chengzhi Huang, Di Li, Chunmei Li. Degradation of dual proteins induced by “power train”[J]. Journal of Pharmaceutical Analysis. doi: 10.1016/j.jpha.2026.101639

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Degradation of dual proteins induced by “power train”

doi: 10.1016/j.jpha.2026.101639

a. Key Laboratory of Biomedical Analytics (Southwest University), Chongqing Science and Technology Bureau, College of Pharmaceutical Sciences, Southwest University, Chongqing, 400715, China;
b. The Pharmacy Department of the Second Hospital of Chongqing Medical University, Chongqing, 400010, China

Funds:

This work was supported by the National Natural Science Foundation of China (Grant Nos.: 22074124 and 22134005), the fund of Fundamental Research Funds for the Central Universities (Grant No.: XDJK2020TY001), the Natural Science Foundation of Chongqing, China (Grant No.: CSTB2022NSCQ–MSX1519), and the fund of Chongqing Municipal Postgraduate Scientific Research Innovation Project, China (Grant No.: CYS25177).

Received Date: Nov. 12, 2025
Accepted Date: Apr. 16, 2026
Rev Recd Date: Apr. 16, 2026
Available Online: Apr. 18, 2026

Abstract

Abstract

Targeted degradation of multiple oncogenic membrane proteins remains challenging due to inefficient lysosomal trafficking and off-target effects, which limits the application of current monovalent aptamer systems. To improve delivery efficiency and degradation efficacy, we developed a specific multivalent network “power train” probe based on rolling circle amplification (RCA) and lysosome-targeting chimera (LYTAC). The probe integrates three functional aptamers: cation-independent mannose-6-phosphate receptor (CI-M6PR) aptamer, responsible for lysosomal trafficking, functions as the “locomotive”; AS1411, which targets nucleolin (NCL), and Sgc8c, which binds to protein tyrosine kinase 7 (PTK7), act as the “carriages”. This tri-aptamer configuration enables simultaneous degradation of both NCL and PTK7. Compared with linear probes, the efficiency of protein degradation is increased by 1.5–1.7 fold, and the enhancement of its cytotoxicity is significantly increased by 4.7–5.8 fold. This network structure’s structure significantly improves binding affinity (the affinity of the network structure is 6.1–6.3 fold higher than that of monovalent aptamers) while enhancing lysosomal degradation efficiency. Removal of any single functional unit will reduce the efficacy of the probe. This “power train” exerts tumor-selective cytotoxicity through dual oncoprotein degradation by coordinately regulating CI-M6PR-mediated lysosomal targeting, AS1411-mediated NCL degradation, and Sgc8c-induced PTK7 degradation, thereby inducing apoptosis and inhibiting proliferation and migration of tumor cells.
- Lysosome-targeting chimera,
- Aptamer,
- Rolling circle amplification,
- Nucleolin,
- PTK7

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References(30)

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