Photo-Switchable Supramolecular Interactions Regulate K⁺ Transmembrane Transport and Cancer Cell Apoptosis

Natural channel proteins (NCPs) have numerous ion transport modes, but it remains a big challenge to replicate this trait by artificial ion transport systems. Herein, we present an azobenzene-incorporated single-chain random heteropolymers (RHPs)-derived biomimetic K⁺ channel <b>P3</b>, which can switch between three ion transport states ("ON," "Partially OFF," and "Totally OFF") in both liposomes and cancer cells. The conformational adjustments of <b>P3</b> activated by light-modulating two groups of supramolecular interactions ((1) hydrogen bonding and π-π interactions; (2) host-guest interactions) realize these switches, resembling the protein mechanisms that govern activity. Underlying molecular mechanisms are the photoisomerization of azobenzene moieties in <b>P3</b> and their complexation with β-cyclodextrin (β-CD), enabling the exploit of a "one stone (azobenzene moiety), two birds (supramolecular interactions)" strategy. Mechanistic investigations demonstrate that <b>P3</b>-induced substantial K⁺ efflux (a 50% drop within just 4 min) causes endoplasmic reticulum (ER) stress, intriguing Ca²⁺ sparks, enhanced reactive oxygen species (ROS), and finally severe mitochondria-dependent apoptosis. This NCP-like channel (<b>P3</b>) is expected to provide new opportunities for a deeper understanding of the internal mechanisms of NCPs, as well as for treating cancer and other diseases.