Enhanced Exosome Immunodetection by Integration of Silica Inverse Opal Architectures as Nanostructured Sensors in Quartz Crystal Microbalance with Dissipation Monitoring

Exosomes are nanosized circulating vesicles that contain biomarkers considered promising for early diagnosis within neurology, cardiology and oncology. Recently, acoustic wave biosensors, in particular based on quartz crystal microbalance with dissipation monitoring (QCM-D), have emerged as a sensitive, label-free, and selective exosome characterisation platform. A rational approach to further improving sensing detection limits relies on the nanostructuration of the sensor surfaces. To this end, inorganic inverse opals (IOs) derived from colloidal self-assembly present a highly tuneable and scalable nanoarchitecture of suitable feature sizes and surface chemistry. This work systematically investigates their use in 2D and 3D for enhanced QCM-D exosome detection. Precise tuning of the architecture parameters delivered improvements in detection performance to sensitivities as low as 6.24 x 10^7 particles/ml. Our findings emphasise that attempts to enhance acoustic immunosensing via increasing the surface area by 3D nanostructuration need to be carefully analyzed in order to exclude solvent and artefact entrapment effects. Moreover, the use of 2D nanostructured electrodes to compartmentalise analyte anchoring presents a particularly promising design principle.