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 IC 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.