Tailoring Infrared\nLight–Molecule Coupling\nfor Highly Sensitive Cortisol Detection Employing Aptamer-Conjugated\nGold Nanonails

Chemically\nsynthesized gold nanoantennas possess easy processability,\nlow cost, and suitability for large-area fabrication, making them\nadvantageous for surface-enhanced infrared (SEIRA) biosensing. Nevertheless,\ncurrent gold nanoantennas face challenges with limited enhancement\nof biomolecular signals that hinder their practical applications.\nHere, we demonstrate that the coupling rate between antennas and molecules\ncritically impacts the enhancement of molecular signals based on temporal\ncoupled mode theory. To improve this coupling rate, we synthesized\ngold nanonails with sharp tips, significantly amplifying the localized\nelectric fields of antenna resonance modes. Modulating the nanonail\naspect ratio allows us to tailor antenna resonance frequencies to\nmatch molecular vibrational frequencies. Additionally, we introduced\nspecific aptamers on antenna surfaces through solution exchange methods\nto control the antenna–molecule distances. These combined strategies\nenabled noninvasive, label-free detection with high sensitivity for\nthe biomarker cortisol. Experiments revealed 3 orders of magnitude\nenhancement in cortisol detection levels upon increasing coupling\nefficiency, achieving a detection limit of 0.1 ng/mL, notably lower\nthan the normal cortisol concentration in human saliva (0.398 ng/mL).\nIn addition to demonstrating a novel strategy for cortisol detection,\nthis study provides a viable approach to biomarker detection for future\napplications in disease diagnosis and human health monitoring.