Controlling Intracellular Enzymatic Self-Assembly of Peptide by Host-Guest Complexation for Programming Cancer Cell...

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 in vitro 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.