Surface Functionalization and Antifouling Engineering of Plasmonic Nanostructures for Optical Biosensing in Complex Biological Media

Plasmonic nanostructures support optical biosensors based on surface plasmon resonance, localized surface plasmon resonance, surface-enhanced Raman scattering, plasmon-enhanced fluorescence, and integrated photothermal or microfluidic readouts. Their translation from bufferoptimized demonstrations to reliable assays in biological media, however, is often limited by the final biointerface rather than by the bare optical transducer. This focused narrative review examines surface functionalization and antifouling engineering as coupled design variables for plasmonic biosensors operating in serum, plasma, saliva, swab-derived fluids, whole blood, wound-associated fluids, and other complex matrices. The literature is organized by interfacial function: anchoring, passivation, bioreceptor coupling, orientation, spacing, hydration, matrix tolerance, regeneration, storage, and quality control. We compare thiol and silane chemistries, silica shells, polydopamine coatings, clickenabled ultrathin layers, poly(ethylene glycol) and oligo(ethylene glycol) interfaces, zwitterionic monolayers and polymer brushes, peptide and nucleic-acid scaffolds, responsive hydrogels, and carbon nanomembranes. Particular attention is given to characterization of the completed biofunctionalized surface, mass-transport and rebinding artifacts, pre-analytical interference, and the distinction between optical sensitivity and assay-level detection capability. Representative real-matrix studies are examined using separate descriptors of sample preparation and validation setting, while Raman quantitation, traceability, machine-learning validation, and point-of-care deployment are discussed through a reporting-focused lens. We propose an interface-first design framework, matrixaware evidence categories, and practical benchmarking tools that separate transducer, biointerface, assay, and translational metrics. The central conclusion is that clinically meaningful plasmonic biosensing depends on a chemically defined, low-fouling, functionally characterized, and reproducible interface that remains quantitatively interpretable in the intended sample