Engineered Reactive Oxygen Species (ROS)‐Responsive Artificial H+/Cl− Ion Channels for Targeted Cancer Treatment

Reactive oxygen species (ROS)-responsive ion channels regulate the ion flow across the membranes in response to alterations in the cellular redox state, playing a crucial role in cellular adaptation to oxidative stress. Despite their significance, replicating ROS-responsive functionality in artificial ion channels remains elusive. In this study, we introduce a novel class of artificial H⁺/Cl^- ion channels activatable by elevated ROS levels in cancer cells. ROS-induced decaging of the phenylboronate group triggers the rapid release of the channel-forming units, leading to self-assembly of the H-bonded cascades facilitating the synergistic transport of H⁺ and Cl^- ions, with H⁺/Cl^- ion transport selectivity of 7.7. Upon activation, ROS-C-Cl exhibits significant apoptotic activity against human breast cancer cells, achieving an IC₅₀ of 2.8 μM, comparable to that of paclitaxel. Exploiting the intrinsic oxidative microenvironment of cancer cells, along with the enhanced oxidative stress arising from H⁺/Cl^- co-transport, ROS-C-Cl demonstrates exceptional selectivity in targeting cancer cells with a selectivity index of 10.2 over normal breast cells, outperforming that of paclitaxel by 19.4 folds.