Spatially Confined Intervention of Cellular Senescence by a Lysosomal Metabolism Targeting Molecular Prodrug for BroadSpectrum Senotherapy
Spatially Confined Intervention of Cellular Senescence by a Lysosomal Metabolism Targeting Molecular Prodrug for BroadSpectrum Senotherapy
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通过溶酶体代谢靶向分子前药对细胞衰老进行空间受限干预，用于广谱衰老治疗
DOI：
10.1002/anie.202115764
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Liu Yanlan
中科院分区：
文献类型：
--
作者：
Xia Yinghao;Li Jili;Wang Linlin;Luo Xiyuan;Xie Yuqi;Liu Yanlan
衰老细胞（SnCs）的特异性干预正在成为对抗衰老和年龄相关疾病的有力手段。规范方法通常被设计为靶向SnC相关的信号传导通路，然而，这些信号传导通路在SnC中是动态变化的并且是高度异质的，这显著地限制了有效性。在这里，我们提出了一种针对溶酶体功能障碍的量身定制的分子前药，这是几乎所有类型的SnCs所共有的独特功能。该前药包含三个模块，均靶向SnC中改变的溶酶体程序，即，针对升高的溶酶体含量的识别单元、可被活化的溶酶体酶裂解的接头和靶向增加的溶酶体膜敏感性的亲溶酶体剂。这种空间受限的设计使得能够杀死广谱SnC，与非SnC相比具有高特异性。沿着体内益处，这项工作提供了一种方法，以显着扩大senotherapy在各种疾病中的适用性。
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.