A Dual‐Channel Synergistic Ultrasensitive Biosensor for Tumor Liquid Biopsy

ABSTRACT Liquid biopsy technology, which detects circulating tumor DNA (ctDNA) in cerebrospinal fluid, plays a crucial role in the early diagnosis and precision treatment of gliomas. However, the intrinsically low abundance and rapid clearance of ctDNA pose substantial challenges for conventional analytical techniques, such as droplet digital PCR and next‐generation sequencing. Here, we introduce a label‐free dual‐channel synergistic detection strategy that enables quantitative analysis of ctDNA at the zeptomolar level. Leveraging a synergistic design that includes structural symmetry breaking and momentum condition regulation, the optical platform overcomes the inherent structural field confinement and enhances the effectiveness of target‐contacted sensing. By integrating a DNA tetrahedron‐hybridization chain reaction‐gold nanoparticle cascade amplification system, the dual‐channel synergistic biosensor achieves an ultra‐low detection limit of 74 zM while covering a dynamic range spanning 12 orders of magnitude. Clinical validation has confirmed that this dual‐channel synergistic detection strategy can accurately identify the IDH1.R132H mutation in glioma patients with as little as 1 µL of sample, and deliver crucial clinical information such as tumor size and staging. This label‐free, rapid, cost‐effective, and highly sensitive biosensing platform offers a powerful tool for early cancer screening, molecular diagnostics, and longitudinal disease monitoring.