Rhodopsin‐Mimicking Reversible Photo‐Switchable Chloride Channels Based on Azobenzene‐Appended Semiaza ‐Bambusurils for Light‐Controlled Ion Transport and Cancer Cell Apoptosis

Abstract The ability to control ion transport across membranes in living systems by stimulus‐responsive natural channels, such as channelrhodopsins and their mimics, is a revolutionary tool for understanding biological processes. Herein, we demonstrate a new class of azo‐functionalized bambusurils (azo‐BUs) that act as efficient, photo‐switchable anion channels capable of modulating chloride flux across lipid membranes and within cellular environments. The ( E )‐isomer exhibits pronounced chloride transport activity, which can be reversibly toggled via light‐induced isomerization, enabling precise spatiotemporal control. Mechanistic studies reveal that the ( E )‐form induces apoptosis through mitochondrial membrane depolarization, reactive oxygen spieces (ROS) generation, and cytochrome c release, while also disrupting lysosomal acidification via H⁺/Cl − cotransport. This dual perturbation of cytosolic and lysosomal ion homeostasis underscores the compound's multifaceted cytotoxic mechanism. In contrast, the ( Z )‐isomer displayed minimal transport activity and negligible cytotoxicity, reinforcing its role as the inactive, photo‐switchable OFF state in this system. The ability to control transport activity with light positions azo‐BUs as promising candidates for the development of next‐generation, stimuli‐responsive anticancer agents. This work introduces a reversible photo‐gated anion channel with therapeutic potential, offering a powerful platform for studying membrane transport and designing light‐responsive biomedical tools.