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Engineering Hierarchical Recognition-Mediated Senolytics for Reliable Regulation of Cellular Senescence and Anti-Atherosclerosis Therapy |
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| Authors: | Yinghao Xia Jili Li Linlin Wang Yuqi Xie Lili Zhang Xiaoyan Han Prof. Weihong Tan Prof. Yanlan Liu |
| Affiliation: | 1. Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan 410082 China These authors contributed equally to this work.;2. Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan 410082 China;3. Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan 410082 China The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022 China Institute of Molecular Medicine (IMM), Renji Hospital, Shanghai Jiao Tong University School of Medicine, and College of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai, 200240 China |
| Abstract: | Precise regulation of vascular senescence represents a far-reaching strategy to combat age-related diseases. However, the high heterogeneity of senescence, alongside the lack of targeting and potent senolytics, makes it very challenging. Here we report a molecular design to tackle this challenge through multidimensional, hierarchical recognition of three hallmarks commonly shared among senescence, namely, aptamer-mediated recognition of a membrane marker for active cell targeting, a self-immolative linker responsive to lysosomal enzymes for switchable drug release, and a compound against antiapoptotic signaling for clearance. Such senolytic can target and trigger severe cell apoptosis in broad-spectrum senescent endothelial cells, and importantly, distinguish them from the quiescent state. Its potential for in vivo treatment of vascular diseases is successfully illustrated in a model of atherosclerosis, with effective suppression of the plaque progression yet negligible side effects. |
| Keywords: | Atherosclerosis Cellular Senescence Hierarchical Recognition Prodrug Senolytics |