High-affinity oxytocin aptamer-based ultrasensitive iontronic classifier for capturing amplified diurnal variation in depressive symptoms

Oxytocin (OT), a neuropeptide with diurnal variation, has been proposed as a candidate biomarker for depression. However, inconsistent findings across clinical studies may stem from both limitations in ultrasensitive detection methods and the neglect of diurnal OT dynamics. Herein, we report the development of high-affinity OT-specific DNA aptamers by systematic evolution of ligands by exponential enrichment (SELEX) and rational engineering, and their integration into an ultrasensitive iontronic classifier coupled with hyperbranched hybridization chain reaction (HB-HCR) amplification. The resulting platform achieved an ultralow detection limit of 2.3 fM and enabled real-time monitoring of OT fluctuations. It successfully tracked dynamic serum OT changes during rat pregnancy and resolved well-defined diurnal variations in human salivary OT. Importantly, patients with depression exhibited elevated OT levels and markedly amplified diurnal amplitudes, which contrasted with the stable patterns observed in healthy individuals. These results establish OT diurnal variation, rather than single-point concentrations, as a sensitive and reliable marker of depressive vulnerability. Beyond this biological insight, the aptamer-integrated iontronic classifier provides a broadly applicable tool for probing low-abundance neuropeptides and opens new avenues for diurnal variation-based mental health risk assessment. Furthermore, machine learning analysis of OT diurnal variation features demonstrated high accuracy in classifying depression, underscoring the potential of this biomarker for objective diagnosis.