Extracellular vesicles (EVs) are routinely released from nearly all cell types as transport vehicles and for cell communication. Crucially, they contain biomolecular content for the identification of health and disease states that can be detected from readily accessible physiological fluids, including urine, plasma, or saliva. Despite their clinical utility within noninvasive diagnostic platforms such as liquid biopsies, the currently available portfolio of analytical approaches are challenged by EV heterogeneity in size and composition, as well as the complexity of native biofluids. Quartz crystal microbalance with dissipation monitoring (QCM-D) has recently emerged as a powerful alternative for the phenotypic detection of EVs, offering multiple modes of analyte discrimination by frequency and dissipation. While providing rich data for sensor development, further progress is required to reduce detection limits and fully exploit the technique’s potential within biosensing. Herein, we investigate the impact of nanostructuring the sensor electrode surface for enhancing its detection capabilities. We employ self-assembly of the block copolymer polystyrene-block-poly(4-vinylpyridine) to create well defined 2D gold islands via selective impregnation of the pyridine domain with gold precursors and subsequent removal of the template. When matched to the EV length scale, we find a 4-fold improvement in sensitivity despite a 4-fold reduction in area for analyte and ligand anchoring in comparison to a flat sensor surface. Creation of tailored and confined sensing regions interspersed by non-binding silica provides optimal spatial orientation for EV capture with reduced steric effects and negative cooperativity of grafted antibodies, offering a promising route for enhanced binding efficiency and performance of sensor platforms.
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.
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