Sub-attomolar-level biosensing of cancer biomarkers using SHG modulation in DNA-programmable quantum dots/MoS ₂ disordered metasurfaces

Detecting biomolecules at ultralow concentrations remains a fundamental challenge in optical biosensing, primarily due to weak light–matter interactions governing signal generation. To address this limitation, we introduce a nonlinear optical sensing platform that leverages second-harmonic generation (SHG) within two-dimensional materials, amplified through quantum-engineered energy transfer. Our approach integrates DNA-programmable nanostructures with monolayer MoS 2 to form disordered metasurfaces that significantly enhance nonlinear optical responses. By precisely positioning individual CdTe/ZnS quantum dots (QDs) at defined distances from the MoS 2 surface using DNA origami scaffolds, we establish highly efficient Förster resonance energy transfer (FRET) pathways, boosting SHG signals by 124.70 fold. Furthermore, the platform incorporates a clustered regularly interspaced short palindromic repeats (CRISPRs) system as a switch: target recognition induces conformational changes that modulate SHG intensity with 93.60% specificity. This integrated material-biology design achieves unprecedented detection limits of 168 zM for microRNAs (miRNAs), representing an improvement of over six orders of magnitude compared to conventional optical biosensors, while retaining single-base discrimination capability. Validation with clinical lung cancer patient samples demonstrated superior diagnostic performance relative to reverse transcription quantitative polymerase chain reaction (RT-qPCR), exhibiting significantly enhanced signal-to-noise ratios in complex biological matrices. Our work establishes a new paradigm in nonlinear optical sensing by demonstrating how engineered quantum interactions can overcome intrinsic limitations of optical detection. This co-design framework, synergizing materials, nanophotonics, and biology, paves the way for next-generation optical diagnostic platforms.