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

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.