Lubricin-Protected Plasmonic Nanoslides Enable Stable, Reusable, Nonfouling, and Ultrasensitive Biomimetic-SERS Sensing for the Detection of Vancomycin in Unprocessed Whole Blood

Surface-enhanced Raman scattering (SERS) is attractive for molecular diagnostics, but direct sensing in unprocessed whole blood is hindered by biofouling and poor operational stability. Here, we report a biomimetic-SERS platform integrating vancomycin-responsive structure-switching aptamers and a self-assembled lubricin (PRG-4) antifouling layer on a nanostructured plasmonic nanoslide. The aptamer provides molecular recognition, while the hydrated glycocalyx-mimicking lubricin layer suppresses nonspecific adsorption from blood and preserves access of vancomycin to the sensing interface. The sensor enables direct vancomycin detection in unprocessed whole blood with subnanomolar sensitivity and retains analytical performance after 3 weeks of storage. It also shows proof-of-concept operational stability, retaining 75% peak intensity across six measurement cycles over more than 5 weeks. Although repeated 20 min UV-Ozone cleaning reduces calibration sensitivity, the nanoslide maintains qualitative detection capability and SERS activity, supporting its potential for point-of-use therapeutic drug monitoring.