Hypoxia-Triggered Adaptive Self-Assembly of Artificial Ion Channels 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 enables the rapid release of channel-forming units, which dimerize into chloride channels or further evolve into nanopores of varying cavity sizes at high concentrations in the presence of cholesterol. Upon activation, the most sensitive channel, <b>C1</b>, demonstrates an 18.1-fold enhancement in cytotoxicity against HepG2 cells with an IC₅₀ of 2.9 μM. Remarkably, <b>C1</b> 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.