Nanoplasmonic Infrared Microarray Sensor Enabling Structural Protein Biomarker‐Based Drug Screening for Neurodegenerative Diseases

Abstract The misfolding of proteins from native monomers into β‐sheet‐rich fibrils via oligomers is a key hallmark of neurodegenerative diseases (NDDs). Identifying and screening drugs that inhibit protein aggregation for early disease intervention remains challenging due to the limitations of existing methods. This work introduces a novel nanoplasmonic infrared microarray sensor for label‐free and high‐throughput drug screening based on structural protein biomarkers in NDDs. The sensor employs 2D arrays of nanoplasmonic units compartmentalized in micropatterned polymeric microwells for high‐throughput protein sensing and secondary structural analysis. The flexibility of the on‐chip integrated microarray sensor is showcased through ultra‐compact 48, 96, and 384 microwell designs, enabling detection from as low as 2 nL of sample volume and with a 100 pg/mL sensitivity in under a minute of in situ measurement. The drug screening capability is validated by assessing multiple drug compounds in a multiplexed manner for their inhibiting effect on aSyn aggregation, an important NDDs protein biomarker. The microarray sensor successfully quantified the secondary structural changes in drug‐treated protein samples, detecting both oligomers and fibrils, which the conventional fluorescence‐based assays failed to do. Thus, the nanoplasmonic microarray sensor is a promising advancement in the NDDs and pharmaceutical research for drug screening.