Chiral Solid-State Nanopores Amplify Secondary Interactions for Ionic-Current Discrimination of Neurotransmitter Enantiomers

Single-molecule ionic-current sensing provides a powerful electroanalytical route for resolving small-molecule enantiomers, yet reliable discrimination remains difficult when stereochemical differences generate only weak and transient interfacial interactions. Here, we engineer a chiral solid-state nanopore by integrating an ultrathin β-cyclodextrin/trimesoyl chloride (β-CD/TMC) nanomembrane onto TiO2 nanopores and confining l-tryptophan within the interfacial host−guest microenvironment. The resulting chiral interface amplifies secondary noncovalent interactions under nanoscale confinement and converts subtle stereochemical asymmetry into distinguishable ionic-current blockade signatures. Using dwell time and normalized current amplitude as event-level descriptors, the nanopore enables high-resolution discrimination of multiple neuroactive enantiomers, including adrenaline (AD), norepinephrine (NE), 3,4-dihydroxyphenylalanine (DOPA), and histidine (His). Structurally related AD and NE enantiomer systems, which differ by only a single methyl group, are resolved in both individual and mixed samples. After chiral interface engineering, the dwell time of d-AD is prolonged by 184%, and a discrimination factor of 42.64 is achieved for mixed analyte systems. Molecular dynamics simulations reveal that the enhanced ionic-current discrimination arises from stereochemistry-dependent persistence and cooperativity of hydrogen bonding and π−π interactions. This work establishes secondary interaction amplification in chiral solid-state nanopores as an effective strategy for single-molecule ionic-current discrimination of complex small-molecule enantiomer systems.