Chiral Gold Nanostructure Monolayers as SERS Substrates for Ultrasensitive Detection of Enantiomer Biomarkers of Alzheimer's Disease

Abstract The early diagnosis of neurodegenerative diseases, such as Alzheimer's disease (AD), requires the identification of sensitive and specific biomarkers. Detecting chiral molecules at concentrations relevant to disease states remains challenging. Herein, a new type of chiral gold nanostructure induced by D‐/L‐cysteine–leucine dipeptides with a g ‐factor of 0.1 was successfully synthesized for enantiomer biomarker detection. To enhance the discrimination performance, the chiral gold nanostructures were assembled into D‐/L‐Au monolayers. As surface‐enhanced Raman scattering (SERS) substrates, the D‐/L‐Au monolayers simultaneously deliver molecular structural specificity and enantioselectivity within a single spectrum, which can be a versatile, label‐free chiral discrimination strategy for the detection of D‐/L‐kynurenine (Kyn). The mechanism was unveiled to involve high enantioselective adsorption energies between L‐ and D‐Kyn on the lattice plane (221), resulting in enantioselective sensing. The results showed that the L‐Au monolayer reached a limit of detection (LOD) of 3.7 n m for L‐Kyn, while the D‐Au monolayer reached an LOD of 3.6 nM for D‐Kyn. Notably, there was a significant difference in D‐Kyn levels between AD patients and healthy individuals in serum samples, a distinction not observed for L‐Kyn, which positioned D‐Kyn as a potential novel biomarker for clinical prediagnosis of AD patients, marking the first report of its kind worldwide. This study provides a robust tool for advancing biomedical science and clinical diagnostics.