Yonsei Advanced Science Institute

Electrochemical sensing techniques for small molecules have progressed in many applications, including disease diagnosis and prevention as well as monitoring of health conditions. However, affinity-based detection for low-abundance small molecules is still challenging due to the imbalance in target-to-receptor size ratio as well as the lack of a highly sensitive signal transducing method. Herein, we introduced nanoscale electrochemistry in affinity-based small molecule detection by measuring the change of quantum electrochemical properties with a nanoscale artificial receptor upon binding. We prepared a nanoscale molecularly imprinted composite polymer (MICP) for cortisol by electrochemically copolymerizing β-cyclodextrin and redox-active methylene blue to offer a high target-to-receptor size ratio, thus realizing “bind-and-read” detection of cortisol as a representative target small molecule, along with extremely high sensitivity. Using the quantum conductance measurement, the present MICP-based sensor can detect cortisol from 1.00 × 10–12 to 1.00 × 10–6 M with a detection limit of 3.93 × 10–13 M (S/N = 3), which is much lower than those obtained with other electrochemical methods. Moreover, the present MICP-based cortisol sensor exhibited reversible cortisol sensing capability through a simple electrochemical regeneration process without cumbersome steps of washing and solution change, which enables “continuous detection”. In situ detection of cortisol in human saliva following circadian rhythm was carried out with the present MICP-based cortisol sensor, and the results were validated with the LC–MS/MS method. Consequently, this present cortisol sensor based on nanoscale MICP and quantum electrochemistry overcomes the limitations of affinity-based biosensors, opening up new possibilities for sensor applications in point-of-care and wearable healthcare devices.