Reaction Kinetics‐Mediated Control over Silver Nanogap Shells as Surface‐Enhanced Raman Scattering Nanoprobes for Detection of Alzheimer's Disease Biomarkers

It is very challenging to accurately quantify the amounts of amyloid peptides Aβ40 and Aβ42, which are Alzheimer's disease (AD) biomarkers, in blood owing to their low levels. This has driven the development of sensitive and noninvasive sensing methods for the early diagnosis of AD. Here, an approach for the synthesis of Ag nanogap shells (AgNGSs) is reported as surface‐enhanced Raman scattering (SERS) colloidal nanoprobes for the sensitive, selective, and multiplexed detection of Aβ40 and Aβ42 in blood. Raman label chemicals used for SERS signal generation modulate the reaction rate for AgNGSs production through the formation of an Ag‐thiolate lamella structure, enabling the control of nanogaps at one nanometer resolution. The AgNGSs embedded with the Raman label chemicals emit their unique SERS signals with a huge intensity enhancement of up to 107 and long‐term stability. The AgNGS nanoprobes, conjugated with an antibody specific to Aβ40 or Aβ42, are able to detect these AD biomarkers in a multiplexed manner in human serum based on the AgNGS SERS signals. Detection is possible for amounts as low as 0.25 pg mL−1. The AgNGS nanoprobe‐based sandwich assay has a detection dynamic range two orders of magnitude wider than that of a conventional enzyme‐linked immunosorbent assay. Silver nanogap shells (AgNGSs) with a controllable nanogap size are prepared by modulating the nucleation reaction kinetics using various Raman label chemicals. AgNGSs are successfully employed as colloidal surface‐enhanced Raman scattering (SERS) nanoprobes emitting intense and stable SERS signals for the sensitive, selective, and multiplexed detection of Alzheimer's disease biomarkers, Aβ40 and Aβ42 in human serum.