A buoyant plasmonic microbubble-based SERS sensing platform for amyloid-beta protein detection in Alzheimer's disease

Amyloid-β (Aβ) plaques are a key pathological hallmark of Alzheimer's disease (AD), highlighting the need for highly sensitive bioassays for Aβ detection to enable AD diagnosis. Here, we synthesized a buoyant plasmonic substrate composed of polyvinyl alcohol microbubbles (MBs) decorated with <i>in situ</i>-reduced gold nanoparticles (Au NPs). Benefiting from its inherent buoyancy and near-infrared plasmonic properties, the Au/MB substrate serves as an ideal platform for biomolecular sensing <i>via</i> the surface-enhanced Raman spectroscopy (SERS) technique. Compared to conventional flat SERS substrates, the three-dimensional (3D) curved surface of the Au/MB substrate significantly increases the effective sensing area, while its inherent buoyancy facilitates the efficient removal of unbound targets, thereby enhancing detection specificity. By functionalizing Au/MB substrates with copper ions (Cu²⁺) and 4-mercaptobenzoic acid (4-MBA), we achieved sensitive detection of AD-related Aβ proteins. In the presence of the target analyte, the interaction between Aβ proteins and Cu²⁺ induces molecular deformation and orientation changes in 4-MBA, leading to distinct spectral changes in the SERS signals. The results demonstrate that the developed Au/MB-based SERS sensor enables sensitive detection of Aβ_1-40 oligomers with a sensitivity as low as 10^-9 M. Therefore, this work not only establishes a foundational framework for designing buoyant plasmonic substrate-based SERS sensing platform but also paves the way for the quantitative detection of disease-associated protein biomarkers, contributing to advancements in AD diagnostics.