Electrochemical Platform Regulated by Cyclodextrin Chiral Microenvironments for Enhanced Enantioselective Recognition

The increasing demand for precise enantiomer recognition in biomedicine highlights the critical importance of highly selective chiral discrimination for optimizing pharmacological efficacy, ensuring drug safety, and elucidating metabolic pathways. Conventional enantioselective high-performance liquid chromatography methods predominantly utilize β-cyclodextrin (β-CD) as a chiral stationary phase, yet their nearly uniform affinity toward l-enantiomers restricts discrimination, particularly for structurally similar species. Herein, we present a sustainable chiral sensing platform constructed via in situ growth of l-tryptophan-functionalized β-CD metal-organic frameworks (<i>l</i> CM/CDMOF) within natural wood channels. Using l- and d-histidine (l/d-His) as model enantiomers, this system enables real-time, quantitative monitoring of chiral signals through a Fenton-like catalytic reaction, in which 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonate) (ABTS) is oxidized by hydrogen peroxide (H₂O₂) to generate ABTS radical cation (ABTS^•+), the formation of which is detected via transmembrane ionic current measurements. To address the challenge of insufficient selectivity, partial embedding of l-tryptophan (l-Trp) into β-CD cavities creates a stereochemically confined microenvironment, markedly enhancing the discrimination of l/d-enantiomer pairs and structurally similar analogs. Molecular docking reveals that distinct hydrogen-bonding networks form between the l-Trp/β-CD system and each enantiomer, providing mechanistic insight into the selectivity enhancement. Integrating cavity occupancy regulation with electrochemical signal amplification, this platform offers a green, efficient, and highly selective strategy for enantiomeric analysis, with broad implications for pharmaceutical, biomedical, and analytical applications.