Spatially Confined Intervention of Cellular Senescence by a Lysosomal Metabolism Targeting Molecular Prodrug for Broad-Spectrum Senotherapy
Yinghao Xia
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.
Search for more papers by this authorJili Li
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.
Search for more papers by this authorLinlin Wang
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
Search for more papers by this authorXiyuan Luo
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
Search for more papers by this authorYuqi Xie
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
Search for more papers by this authorCorresponding Author
Prof. Yanlan Liu
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
Search for more papers by this authorYinghao Xia
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.
Search for more papers by this authorJili Li
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.
Search for more papers by this authorLinlin Wang
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
Search for more papers by this authorXiyuan Luo
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
Search for more papers by this authorYuqi Xie
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
Search for more papers by this authorCorresponding Author
Prof. Yanlan Liu
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
Search for more papers by this authorGraphical Abstract
A spatially confined prodrug activation strategy is reported as a new paradigm of senotherapy. The prodrug is designed to target the defective lysosome metabolism, a unique yet ubiquitous event during cellular senescence, instead of dynamically changing and highly heterogeneous senescence-related signaling pathways employed in conventional methods, thereby fulfilling robust specificity and broad-spectrum activity towards senescent cells.
Abstract
Specific intervention of senescent cells (SnCs) is emerging as a powerful means to counteract aging and age-related diseases. Canonical methods are generally designed to target SnC-associated signaling pathways, which are however dynamically changing and highly heterogeneous in SnCs, significantly limiting the effectiveness. Here, we present a tailor-made molecular prodrug targeting lysosome dysfunction, a unique feature shared by virtually all types of SnCs. The prodrug comprises three modules all targeting the altered lysosomal programs in SnCs, namely, a recognizing unit towards the elevated lysosome content, a linker cleavable by the activated lysosomal enzyme, and a lysosomotropic agent targeting the increased lysosomal membrane sensitivity. This spatially confined design enables killing broad-spectrum SnCs, with high specificity over non-SnCs. Along with in vivo benefits, this work offers a way to significantly expand the applicability of senotherapy in a wide range of diseases.
Conflict of interest
The authors declare no conflict of interest.
Open Research
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Supporting Information
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