Quantitative Sensing of Monosaccharide Isomers with High Resolution and Attomolar Limit of Detection

The quantitative detection of monosaccharide isomers holds significant promise for both the diagnosis of metabolic diseases and the development of carbohydrate-based pharmaceuticals. However, highly selective discrimination and trace detection of these isomers remain challenging. Herein, we reported a novel single-molecule tunneling sensor for the quantitative detection of glucose isomers with high performance. By directly characterizing the intrinsic conductance of single-molecule junctions formed by dynamic boronic ester bonding, we achieved a dramatic ∼60-fold difference in conductance signals for discrimination of glucose isomers. Furthermore, by integrating artificial-intelligence-based unsupervised data clustering, we realized quantitative sensing of glucose isomers with an ultrawide linear range from ∼0.1 fM to 0.1 mM and an ultralow limit of detection of 59 aM. Theoretical calculations revealed that the high selectivity originates from the stability energy difference of a single-molecule junction formed by different monosaccharide isomers. Our work establishes a paradigm for single-molecule stereochemical analysis, offering potential for ultrasensitive bioanalysis and drug discovery.