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  3. Engineering Hierarchical Recognition-Mediated Senolytics for Reliable Regulation of Cellular Senescence and Anti-Atherosclerosis Therapy

Engineering Hierarchical Recognition-Mediated Senolytics for Reliable Regulation of Cellular Senescence and Anti-Atherosclerosis Therapy

  • Angew Chem Int Ed Engl. 2023 Jan 23;62(4):e202214169. doi: 10.1002/anie.202214169.
Yinghao Xia 1,  Jili Li 1,  Linlin Wang 1,  Yuqi Xie 1,  Lili Zhang 1,  Xiaoyan Han 1,  Weihong Tan 1 2 3,  Yanlan Liu 1
Affiliations

Affiliations

  • 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.
  • 2 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.
  • 3 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.
PMID: 36445796 DOI: 10.1002/anie.202214169
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.

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