Key Laboratory of Precise Synthesis of Functional Molecules of Zhejiang Province, School of Science, Department of Chemistry, Westlake University; Institute of Natural Sciences, Westlake Institute for Advanced Study, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China.
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China.
Nano Lett. 2022 Sep 28;22(18):7588-7596. doi: 10.1021/acs.nanolett.2c02612. Epub 2022 Aug 4.
Controlling the enzymatic reaction of macromolecules in living systems plays an essential role in determining the biological functions, which remains challenging in the synthetic system. This work shows that host-guest complexation could be an efficient strategy to tune the enzymatic self-assembly of the peptide. The formed host-guest complexation prevents the enzymatic kinetics of peptide assemblies on the cell surface and promotes cellular uptake of assemblies. For uptake inside cells, the host-guest complex undergoes dissociation in the acidic lysosome, and the released peptide further self-assembles inside the mitochondria. Accumulating assemblies at mitochondria induce the ferroptosis of cancer cells, resulting in cancer cell death and the tumor-bearing mice model. As the first example of using host-guest complexation to modulate the kinetics of enzymatic self-assembly, this work provides a general method to control enzymatic self-assembly in living cells for selective programming cancer cell death.
控制生物体系中大分子的酶促反应对于确定其生物学功能至关重要，但在合成体系中这仍然具有挑战性。本工作表明，主客体络合作用可以成为一种有效的策略来调节肽的酶促自组装。形成的主客体络合物可以阻止肽在细胞表面的酶促动力学组装，并促进组装体的细胞摄取。对于进入细胞内的摄取，主体-客体络合物在酸性溶酶体中发生解离，释放的肽进一步在线粒体内部自组装。在积累在线粒体的组装物会诱导癌细胞发生铁死亡，导致癌细胞死亡和荷瘤小鼠模型死亡。作为首例使用主客体络合作用来调节酶促自组装动力学的例子，本工作为在活细胞中控制酶促自组装以选择性编程癌细胞死亡提供了一种通用方法。
