文献类型：期刊文献

英文题名：Programmable DNA Origami-Based Protease Device for Precise and Direct Proteins Degradation

作者：Liu, Yue[1];Cheng, Hui-Juan[1];Liu, Yi-Shan[1];Shi, Wen-Jia[1];You, Di[1];Ma, Pei-Qiang[1];Ye, Bang-Ce[1]

机构：[1]East China Univ Sci & Technol, Lab Biosyst & Microanal, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China

年份：2026

卷号：148

期号：14

起止页码：15246

外文期刊名：JOURNAL OF THE AMERICAN CHEMICAL SOCIETY

收录：;EI(收录号：20261720579529);WOS:【SCI-EXPANDED(收录号:WOS:001732718900001)】；

基金：This work was jointly supported by the National Key Research and Development Program of China (Grant 2024YFA0917100), the Natural Science Foundation of Shanghai (Grant 25ZR1403002), the National Natural Science Foundation of China (Grant 22134003), and the Fundamental Research Funds for the Central Universities. We thank the Research Center of Analysis and Test of East China University of Science and Technology for the help on the characterization experiments. We thank the staff members of the Integrated Laser Microscopy System/Molecular Imaging System at the National Facility for Protein Science in Shanghai (NFPS) (Shanghai Advanced Research Institute, Chinese Academy of Sciences) for AFM data collection and analysis.

语种：英文

外文关键词：Biodegradation - Degradation - Proteins - Proteolysis

摘要：Targeted protein degradation as a therapeutic modality leverages cellular proteolytic pathways to specifically eliminate disease-associated proteins. However, the dependence on endogenous pathways limited its further development in safety and universality. We fabricate a DNA origami-based protease device (DOPD) for extracellular direct degradation of tumor-associated proteins by regulating the activity of the protease. The DOPD features a six-helix bundle structure with a dual-functional architecture: an inner catalytic layer assembling proteases and trap strands and an outer shielding layer decorated with poly(lactic-co-glycolic acid) to limit the protease activity. By incorporating a pH-sensitive switch and a recognition module, this system enables direct protein degradation by inducing proximity between target proteins and proteases. We demonstrate that this system specifically degrades nucleolin and PD-L1 on tumor cells under acidic conditions, exerting direct cytotoxicity on tumor cells and alleviating immunosuppression in immune cells. As a proof of concept, DOPD-mediated tumor immunotherapy was validated in a xenograft mouse model, underscoring its potential as a programmable platform for precise protein degradation.