Programmable Artificial K⁺-Cl- Cotransporters Harness K⁺ Flux to Drive Secondary Active Chloride Transport

Natural K+-Cl- cotransporters (KCCs) are secondary active transporters that move Cl- against its transmembrane concentration gradient by harnessing the electrochemical gradient of K+. Faithfully replicating this secondary active transport function synthetically requires precisely balanced control of K+/Cl- ion selectivity. Here, we report the first class of artificial K+-Cl- cotransporter system capable of such a secondary active transport, enabled by a dual-channel strategy that provides controllable bidirectional tuning of K+/Cl- selectivity within a single structural framework. The system features a modular, amino acid–derived H-bonded backbone that assembles into a one-dimensional array, positioning crown ether units on one side for K+ transport while hydrocarbon chains on the opposite side form anion-conducting pores. Independent variation of crown ether size and alkyl chain length enables fine control of transport properties, favoring K+ over Cl- without excessive selectivity and thereby allowing passive K+ flux to drive uphill Cl- transport in an unprecedented manner. The top-performing AKCC, 6F12, exhibits a balanced K+/Cl- selectivity ratio of 2.48 and enables robust K+-driven secondary active Cl- transport in a simulated cardiomyocyte environment. This work establishes a versatile design paradigm for controllable secondary active transport of Cl- anions, bridging a critical gap between biological inspiration and functional biomimetic materials.