A Reversible Light‐Driven Biomimetic K⁺/Na⁺‐Exchanger Controls Cancer Cell Apoptosis

Abstract Although natural dual‐ion exchangers are indispensable for bio‐organic functions, developing their artificial counterparts remains nearly unexplored. Herein, this work proposes a novel light‐controlled K⁺/Na⁺‐transport‐exchanger TE12, realizing an unprecedented reversible switch between K⁺‐ and Na⁺‐transmembrane transport by changing its transport mechanism (channel and carrier). The conformational transformation of the azobenzene moiety in TE12 essentially induces this. The K⁺/Na⁺ selectivity of K⁺‐channel Trans‐TE12 is as high as 20.3, making it one of the most selective artificial K⁺‐transporters. Moreover, considering the scarcity of artificial Na⁺‐transporters, the Na⁺‐carrier Cis‐TE12 with high Na⁺/K⁺ selectivity (9.25) represents a breakthrough. Cis‐TE12 significantly triggers cell apoptosis by igniting fascinating “Na⁺ sparks” first observed on cancer cells treated with synthetic channels, while K⁺‐channel Trans‐TE12 exhibits low toxicity. Importantly, TE12 can function as a spatiotemporally controllable ion interference therapy, enabling in situ 365 nm light‐triggered and 450 nm light‐inhibited cell death. This work realizes sophisticated functions in a simplified structure by the “Less is More” design concept. It opens a shortcut toward the future iterative updating of artificial ion transporters to make them better biological analogs and therapeutic agents.