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

## TL;DR

This paper discusses a new method using enzyme-coupled supramolecular systems to detect biomolecules with high selectivity and accuracy.

## Contribution

The paper introduces a supramolecular tandem assay that combines macrocyclic reporter pairs with enzymatic transformations for selective biomolecule detection.

## Key findings

- The supramolecular tandem assay achieves selective detection of choline and acetylcholine at micromolar concentrations.
- The enzymatic step enhances molecular specificity and the host–dye displacement mechanism allows tunable signal output.
- This strategy overcomes limitations of conventional macrocyclic hosts while maintaining broad applicability.

## Abstract

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.

In celebration of our 15th anniversary and some of our most popular articles, Yu Liu reflects on the area of supramolecular tandem assays, building on a Chemical Science manuscript published in 2011 on this topic [Guo et al. (Chem. Sci., 2011, https://doi.org/10.1039/C1SC00231G)].