Interfacial Charge-Regulated DNA Nanonets Enable Polarity-Switching Photoelectrochemical Liquid Biopsy of Lung Adenocarcinoma Circu-lating Tumor Cells

Conventional clinical diagnostic of lung adenocarcinoma relies heavily on computed tomography imaging combined with tissue biopsyan invasive workflow that drastically limits patient compliance and impedes early screening and dynamic monitoring. Although circulating tumor cells (CTCs) enable minimally invasive disease tracking, their clinical detection is severely compromised by ultralow abundance and complex hematological interferences. Herein, we present a dye-induced signal-reversal photoelectrochemical (PEC) biosensor for sensitive and accurate CTC detection in raw whole blood. Specific CTC recognition triggers a Mg2+-dependent DNAzyme-cascaded amplification, yielding abundant single-stranded DNA that programmably assembles into an acriflavine-confined nanonet at the electrode interface. This engineered nano-biointerface alters charge-transfer kinetics, thus driving a distinct anodic-to-cathodic photocurrent transition to effectively eliminate background noise and improve signal reliability, enabling ultrasensitive CTC quantification across a broad linear range (10−105 cells·mL−1) and an ultralow detection limit (0.11 cell·mL−1), along with excellent selectivity, stability, and reproducibility. Notably, clinical validation of the proposed biosensor using whole blood samples from lung adenocarcinoma patients (n = 78) and healthy donors (n = 22) shows high diagnostic accuracy (area under the curve = 0.9129) and strong consistency with radiologic findings. This engineered PEC sensing platform offered a robust, minimally invasive liquid biopsy strategy for early lung adenocarcinoma screening, therapeutic response assessment, and longitudinal disease management in personalized medicine.