Self-aggregated photo-heterostructures enhancing fluorescence for cancer diagnosis and treatment monitoring

Semiconductor zinc oxide (ZnO) nanostructures as classic photonic materials have sparked the development of low-cost, high-performance fluorescence sensors; however, their scalable clinical applications remain hampered by inadequate sensitivity. Here, we engineer a high-curvature photo-heterostructure aggregate-enhanced fluorescence (PAEF) sensor based on bubble-scaffolded ZnO nanorods. Leveraging synergistic evanescent field coupling and self-aggregation of photo-heterostructures, PAEF sensor streamlines efficient isolation (~90%) and ultrasensitive profiling of tumor extracellular vesicles (EVs) in a single assay, achieving sensitivity <10 EVs/μL (104-fold better than ELISA) without additional amplification, outperforming most state-of-the-art EV fluorescence assays. This self-sufficient sensor enables accurate monitoring of targeted therapeutic efficacy in mouse xenograft models via simultaneous dual-marker readout. We further show its clinical utility in hepatocellular carcinoma diagnosis with ≥96% accuracy (≥98% specificity) in two cohorts (n = 146), improving dynamic monitoring of surgical treatment responses, particularly in alpha-fetoprotein-negative patients. This work provides a cost-effective ultrasensitive liquid biopsy tool advancing non-invasive cancer diagnosis. Fluorescent detection approaches often require specialist equipment or have limited sensitivity. Here, the authors develop a bubble-scaffolded zinc oxide nanorod photo heterostructure aggregate for fluoresce enhancement demonstrating application for detection of circulating extracellular vesicles.