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

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.