Integrating terahertz metamaterial and water nanodroplets for ultrasensitive detection of amyloid β aggregates in liquids

•Water nanodroplets are introduced for liquid samples to enhance the signal-noise ratio of terahertz spectroscopy.•The combination of metamaterial and nanoconfined space is used to further increase the sensitivity.•The nanodroplet terahertz sensor can sensitively detect amyloid β with 1 nM limit. The association of amyloid β (Aβ) peptide and its ordered aggregates with the onset of Alzheimer’s disease raises the rational use as biomarker for therapeutic and diagnostic. However, due to the heterogeneity among aggregates and relatively low concentration at the physiological conditions, the fast and sensitive detection of the Aβ aggregates remains technical challenges. In this work, we develop a label-free method for probing the hydration dynamics of collective Aβ aggregates in liquids by using terahertz spectroscopy. Aβ aggregates-containing water nanodroplets provide an aqueous confinement environment for improving signal-to-noise ratio of terahertz response. The integration of a metamaterial sensor and nanoconfined droplets further extremely enhances the sensitivity and enables to detect 1 nM Aβ aggregates in a buffer solution. This novel development offers a valuable toolkit towards bioanalytical applications in neurobiology but also paves the way for tracing the ultrafast dynamic biological process in fundamental science.