Aromatic Interaction‐Driven Adaptive Transformation of Macrocyclic Unimolecular Chloride Channels Into Nanopores

ABSTRACT Biological ion channels and pores frequently exhibit dynamic, concentration‐dependent adaptive assembly, yet synthetic systems that faithfully replicate this intriguing behavior remain rare. In this study, we present a novel class of tripeptide‐appended macrocyclic ion channels that undergo aromatic interaction‐driven adaptive transformation from unimolecular chloride channels into higher‐order nanopores. At low concentrations, analogues with aromatic tripeptide‐functionalized macrocycles ( MC‐F and MC‐W ) function as discrete and efficient chloride channels. Upon increasing the concentration, cooperative aromatic interactions among the tripeptide side chains promote their lateral self‐assembly into stable nanopores, enabling efficient transmembrane transport of small molecules, including carboxyfluorescein and glucose. In contrast, the aliphatic analogues ( MC‐A , MC‐L , and MC‐I ) remain restricted to unimolecular chloride channels. Single‐channel measurements combined with theoretical calculations further substantiate the structural stability and energetic preference of tetrameric and pentameric assemblies within lipid bilayers. Collectively, this work establishes cooperative aromatic interactions as a versatile and robust design principle for engineering adaptive artificial channels, thereby narrowing the functional gap between synthetic systems and the dynamic regulatory behavior of natural channels.