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

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 (EC₅₀: 0.72 µm for G3C7; 0.9 µm 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 Ca²⁺ 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.