Proton‐Activated Artificial Channels for pH‐Selective Cancer Therapy

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 IC₅₀ 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.