Tailoring Infrared Light–Molecule Coupling for Highly Sensitive Cortisol Detection Employing Aptamer-Conjugated Gold Nanonails

Chemically synthesized gold nanoantennas possess easy processability, low cost, and suitability for large-area fabrication, making them advantageous for surface-enhanced infrared (SEIRA) biosensing. Nevertheless, current gold nanoantennas face challenges with limited enhancement of biomolecular signals that hinder their practical applications. Here, we demonstrate that the coupling rate between antennas and molecules critically impacts the enhancement of molecular signals based on temporal coupled mode theory. To improve this coupling rate, we synthesized gold nanonails with sharp tips, significantly amplifying the localized electric fields of antenna resonance modes. Modulating the nanonail aspect ratio allows us to tailor antenna resonance frequencies to match molecular vibrational frequencies. Additionally, we introduced specific aptamers on antenna surfaces through solution exchange methods to control the antenna–molecule distances. These combined strategies enabled noninvasive, label-free detection with high sensitivity for the biomarker cortisol. Experiments revealed 3 orders of magnitude enhancement in cortisol detection levels upon increasing coupling efficiency, achieving a detection limit of 0.1 ng/mL, notably lower than the normal cortisol concentration in human saliva (0.398 ng/mL). In addition to demonstrating a novel strategy for cortisol detection, this study provides a viable approach to biomarker detection for future applications in disease diagnosis and human health monitoring.