Proton‐Activated Artificial Channels for pH‐Selective Cancer Therapy

ABSTRACT Proton‐activated ion channels mediate ion transport in response to extracellular acidification, enabling cellular adaptation to acidic microenvironments. Despite their biological importance, mimicking proton‐activated functionality in artificial ion channels remains a significant challenge. Here, we present a novel class of proton‐activated artificial ion channels built from self‐assembled peptide chains integrated into a pH‐responsive 2,2′‐bipyridine scaffold. Protonation induces a conformational switch in the channel‐forming units, promoting one‐dimensional self‐assembly and subsequent hydrophobic packing into functional channels capable of transporting small molecules. As extracellular pH decreases from 7.4 to 6.5, C‐FF exhibits a 10.3‐fold enhancement in cytotoxicity against human colorectal carcinoma cells, boosting an IC 50 of 2.8 µM, mediated through apoptosis induction and cell cycle arrest resulting from disruption of the autophagic process. Significantly, C‐FF demonstrates exceptional selectivity for cancer cells, achieving a selectivity index of 8.5, surpassing that of doxorubicin by one order of magnitude while maintaining comparable potency, highlighting its potential as a pH‐responsive platform for selective anticancer therapy in acidic tumor microenvironments.