A Temperature‐Sensitive Dual Ion Channel Based on Quinoline Helix for H + /Cl − Cotransport With Remarkable Antitumor Effect

ABSTRACT Synthetic ion channels with efficient ion transport activity can disrupt the ion homeostasis of cancer cells and exhibit potential for tumor therapy. Herein, a helix‐based ion channel was constructed via a one‐pot synthesis strategy. This channel is composed of two interconnected proton channel (quinoline helix) and chloride ion channel (aligned thiourea moieties), which is named as “dual ion channel.” This dual ion channel can insert into the phospholipid membrane through a single‐molecule form and flux H + and Cl − across the membrane simultaneously. Interestingly, this dual ion channel also exhibits “ON‐OFF” switchable ion transport behaviors in response to external temperature variation. Under physiological environment (37°C), this channel achieves highly efficient ion transport and reveals remarkable anticancer activity against U87 cells with an IC 50 value of 0.14 µM, which is comparable to commercial chemotherapy drugs. The mechanism induces mitochondrial membrane potential loss and destabilizes subcellular organelles, including lysosomes, leading to the release of reactive oxygen species (ROS) and cytochrome c, which ultimately activates the intrinsic apoptosis pathway and results in programmed cell death of tumor cells. This dual ion channel not only serves as a potent anticancer agent but also provides an entry point for future design of functional ion channels.