Reversible redox-controlled semiaza-bambusuril chloride channels for targeted cancer therapy

Artificial ion transporters offer promising avenues for therapeutic intervention by disrupting ionic homeostasis in cancer cells. Herein, we report the design, synthesis, and biological evaluation of a novel class of redox-switchable chloride channels based on selenide-containing semiaza-bambusurils. These macrocyclic compounds exhibit reversible transmembrane chloride transport activity modulated by the oxidation state of selenium side chains, enabling precise control over ion flux in response to cellular redox conditions. The reduced selenide form facilitates efficient H⁺/Cl⁻ symport across lipid bilayers, thereby inducing apoptosis and inhibiting autophagy in cancer cells. Oxidation to selenoxide suppresses transport activity due to increased hydrophilicity, which is restored upon reduction by intracellular glutathione (GSH), demonstrating a dynamic ON/OFF switching mechanism. Single-channel conductance studies confirm unimolecular channel formation, and in vitro assays reveal potent cytotoxicity against multiple cancer cell lines. Cell-intrinsic mechanism studies have revealed an unusual, ultrafast form of cancer cell death induced by perturbation of intracellular chloride concentrations, leading to apoptotic cell death and the inhibition of autophagy. In vivo experiments using U87MG tumor-bearing mice show significant tumor growth inhibition with minimal systemic toxicity. This work represents the first example of a bambusuril-based artificial ion channel with reversible redox control and in vivo efficacy, offering a powerful platform for adaptive, targeted cancer therapies.