A reflection on enzyme-coupled supramolecular sensing: overcoming selectivity barriers with macrocyclic reporter pairs.

Macrocycle-based supramolecular sensing systems have emerged as a powerful approach for biomolecular detection, yet practical applications remain challenging in inadequate selectivity toward structurally similar analytes, low signal-to-noise ratios, and environmental interference. Liu et al. (D.-S. Guo et al., Chem. Sci., 2011, 2, 1722-1734, https://doi.org/10.1039/C1SC00231G) developed a novel "supramolecular tandem assay" by integrating the p-sulfonatocalix[n]arene·lucigenin (LCG) host-guest reporter pairs with enzymatic transformations, achieving highly selective, label-free detection of choline and acetylcholine at physiologically relevant micromolar concentrations. The enzymatic step confers molecular specificity absent in conventional macrocycle-based sensors, while the host-dye displacement mechanism provides a tunable signal output. This strategy overcomes inherent limitations of conventional macrocyclic hosts while preserving their broad applicability, providing transformative opportunities for real-time enzyme activity monitoring and Alzheimer's drug screening.