Sub-attomolar-level biosensing of cancer biomarkers using SHG modulation in DNA-programmable quantum dots/MoS2 disordered metasurfaces

Recent advances in nonlinear optical biosensing have revealed the critical role of 2D material heterostructures in amplifying second-harmonic generation (SHG). Here, we present a paradigm-shifting biosensing architecture that synergizes atomically precise DNA origami nanotechnology with monolayer quantum dot (QD)/MoS2 disordered metasurfaces, achieving unprecedented single-molecule sensitivity in clinical oncology. By strategically engineering DNA origami nano-spacing architectures, we successfully established Förster resonance energy transfer (FRET) pathways between CdTe/ZnS QDs and MoS₂ excitonic hotspots, which induce 124.70-fold SHG amplification. CRISPR signal dynamics enable target-specific QD release with 93.60% cleavage specificity, demonstrating dynamic signal modulation in complex biological fluids. The system achieves real-time signal modulation resolving microRNAs (miRNAs) at 168.34 zM with single-base discrimination. Demonstrating clinical translational potential, our platform achieved superior diagnostic performance in lung cancer patient samples, validated through the comparison with RT-qPCR. Our findings demonstrate enhanced sensitivity and specificity for key biomarker detection, establishing a new benchmark in clinical settings. This work pioneers a "materials-nanophotonics-biology" co-design framework, redefining the frontiers of optical molecular diagnostics.