Mechanosensitive and pH‐Gated Butterfly‐Shaped Artificial Ion Channel for High‐Selective K⁺ Transport and Cancer Cell Apoptosis

Abstract

Abstract To advance the exploration of mechanisms underlying natural multi‐gated ion channels, a novel butterfly‐shaped biomimetic K + channel GnC7 (n = 3, 4) is developed with dual mechanical and pH responsiveness, exhibiting unprecedented K + /Na + selectivity ( G3C7 : 34.4; G4C7 : 41.3). These channels constructed from poly(propylene imine) dendrimer and benzo‐21‐crown‐7‐ethers achieve high K + transport activity (EC 50 : 0.72 µ m for G3C7 ; 0.9 µ m for G4C7 ) due to their arc‐like mechanical rotation. The dynamic mode relies on butterfly‐shaped topology derived from the highly symmetrical core and multiple intramolecular hydrogen bonds. GnC7 can sense mechanical stimulus applied to liposomes/cells and then adapt the K + transport rate accordingly. Furthermore, reversible ON/OFF switching of K + transport is realized through the pH‐controllable host‐guest complexation. G4C7 ‐induced ultrafast cellular K + efflux (70% within only 9 min) efficiently triggers mitochondrial‐dependent apoptosis of cancer cells by provoking endoplasmic reticulum stress accompanied by drastic Ca 2+ sparks. This work embodies a multi‐dimensional regulation of channel functions; it will provide insights into the dynamic behaviors of biological analogs and promote the innovative design of artificial ion channels and therapeutic agents.