Bioinspired Chemosensor with Configuration-Dependent Affinity for Localized Tracking of Labile Zn²⁺ during Neuronal Differentiation

Homeostasis and transportation of labile Zn²⁺ across neuronal membranes are of great importance for biological functions, in which molecular tools are urgently demanded to understand the mechanism of actions in depth. Here, we report a zinc-specific fluorescence-switchable chemosensor (<i>trans</i> T-P) for the targetable tracing of labile Zn²⁺ in live nerve cells. The molecular design was inspired by the coordination structure in the catalytic centers of metalloenzymes. The strong coordination and response to Zn²⁺ were demonstrated to be stereochemistry-sensitive, in which only the <i>trans</i> conformer has ultrahigh affinity, selectivity, and sensitivity. Benefited from its amphiphilic and phosphate-bearing molecular structure, <i>trans</i> T-P is readily cell membrane permeable and achieves preferential accumulation in the near-membrane region, enabling regionally specific localization and imaging of labile Zn²⁺ at the intracellular side of plasma membranes. Provided with these unique properties, <i>trans</i> T-P achieved an in situ visualization of labile Zn²⁺ fluctuations during neuronal differentiation. The targeted sorting and tracking highlight the prominence of <i>trans</i> T-P in monitoring Zn²⁺ spatiotemporal dynamics for understanding the actions of labile Zn²⁺ in nerve functions and development.