Hydrodynamic−Plasmonic Au@ZIF-8 Nanoarray Sensor for Ultrasensitive DNA Methylation Assay toward Early Cancer Detection

DNA methylation has emerged as a pivotal molecular biomarker for early cancer diagnosis. Nevertheless, existing detection strategies remain limited by complex workflows, poor efficiency in trace DNA capture, and the inability to resolve both absolute concentration and methylation ratio simultaneously. Herein, we engineer a tilted fiber Bragg grating (TFBG) biosensor functionalized with Au@zeolitic imidazolate framework-8 (Au@ZIF-8) core-shell nanoparticle arrays. This architecture overcomes the diffusion-limited capture of conventional biosensors through a powerful hydrodynamic-plasmonic synergy. First, hydrodynamic stagnation flow efficiently preconcentrates trace DNA molecules onto the sensing interface. Subsequently, plasmon-enhanced dielectrophoresis provides an active trapping force, precisely localizing these molecules onto sensing hotspots. To enable multiparametric methylation profiling, a dual-recognition strategy was developed by integrating sequence-specific DNA hybridization with 5-methylcytosine (5mC) antibody binding. This approach allows for rapid (<15 min), amplification-free quantification of both methylated DNA concentration and methylation ratio in complex biological samples, with an ultralow detection limit of 6.9 × 10² copies/μL. Clinical validation using patient-derived samples demonstrates excellent diagnostic accuracy, achieving a receiver operating characteristic (ROC) area under the curve (AUC) of 0.941 through multilocus methylation analysis. This study establishes a robust, amplification- and label-free biosensing platform that integrates microfluidic manipulation with plasmonic nanoengineering, offering a powerful strategy for high-throughput, clinically translatable DNA methylation analysis in early cancer detection.