A Bilingual Nanobiosensor for Cross-Category Integrated Decoding of the Beta-Site Amyloid Precursor Protein-Cleaving Enzyme 1–Aβ Oligomer Signaling Pathway

Herein, a sequentially responsive peptide DNA bilingual nanobiosensor is developed, which allows integrated quantification of amyloid signaling pathway. In this system, upstream beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1) protease and downstream Aβ oligomer (AβO) are designed as two inputs for the AND DNA logic gate. In the existence of both inputs, peptide substrate with aptamer can be sequentially cleaved, reporting electrochemical and fluorescence dual-mode outputs. In comparison with conventional single protease activity assay based on peptide nanotechnology, this strategy permits accurate diagnosis of Alzheimer's disease (AD) from normal subjects. More importantly, it can achieve distinguished diagnosis between AD and type 2 diabetes mellitus patients. This bilingual nanobiosensor is successfully applied to detect BACE1 (1–100 U mL⁻¹) and AβO (5–1000 pg mL⁻¹) with limit of detections as low as 0.10 U mL⁻¹ and 0.76 pg mL⁻¹, respectively. Furthermore, this strategy inspires advanced nanobiosensors to target the activation of other signaling pathways, which are potential tools for future biology and medicine investigation.