Smart Adaptive Artificial Channels Triggered by Hypoxia for Highly Selective Apoptosis in Cancer Cells

In nature, hypoxia-sensitive ion channels regulate the ion transport in response to oxygen levels, which are critical for cellular adaptation to low-oxygen environments. However, this intriguing stimuli-responsive property has yet to be replicated in artificial ion channels designed to mimic the essential functions of their natural counterparts. Herein, we introduce a novel class of adaptive artificial channels activatable under hypoxic conditions in cancer cells. Reductase-mediated reduction of nitro and/or azo groups triggers the rapid release of channel-forming units, which dimerize into chloride channels or further assemble into nanopores of varying cavity sizes at high concentrations in the presence of cholesterol. Upon activation, the most sensitive channel, C1, demonstrates an 18.1-fold enhancement in cytotoxicity against HepG2 cells with an IC₅₀ of 2.9 µM. Remarkably, C1 exhibits exceptional selectivity for liver cancer cells over normal liver cells, with a selectivity index of 17.9, surpassing that of doxorubicin by 44.8 folds while maintaining comparable anticancer efficacy.