Plasmonic Interfaces for Advanced Profiling of Cell-Free Circulating Biomarkers

Cell-free circulating biomarkers, including extracellular vesicles (EVs) and EV-free biomarkers, hold significant potential as minimally invasive, real-time indicators of disease states. They abound in bodily fluids, are analytically stable, and possess exceptional diversity─biophysical and biomolecular─to provide a wealth of accessible information for personalized medicine. Despite their potential, the clinical use of cell-free biomarkers is challenged by their diversity in size and biomolecular composition as most existing analytical technologies are limited to match the spectrum. Surface plasmon resonance (SPR) offers a promising solution with its excellent compatibility; central to this superior tunability lies the remarkable engineering of plasmonic interfaces to accommodate biomarkers of varying sizes and biomolecular composition. Motivated by these developments, in this review, we introduce key characteristics of cell-free circulating biomarkers, overview distinct mechanisms of plasmonic sensing, and highlight state-of-the-art design and application of different plasmonic interfaces─by colloidal nanoparticles and arrayed nanostructures─for enhanced detection of cell-free biomarkers. Finally, we discuss future opportunities in technology development to facilitate biomarker discovery and clinical translation for next-generation personalized medicine.