A Biomimetic Nanozyme Engineered via Coordination and Confinement for Photothermal-Reinforced Catalytic Detection of Extracellular Vesicles and Diagnosis of Cancer.

Extracellular vesicles (EVs) have emerged as promising biomarkers for liquid biopsy. However, their clinical detection is hampered by heterogeneity and low abundance. Herein, a dual-mode biosensor is constructed based on a biomimetic nanozyme for the highly sensitive and selective detection of tumor-derived EVs (tEVs). The biomimetic nanozyme is engineered through a dual-preservation effect involving coordination and confinement. In this design, the Fe2+-coordinated graphene quantum dots (Fe-GQDs, denoted as Fe-G) are spatially confined within DNA flower-like structures (Fe-G@DFs). This architecture effectively stabilizes the low-valence state of Fe2+ as the catalytically active center and enhances the peroxidase (POD)-like activity of the nanozyme. This system features an enzymology-inspired biomimetic activation, where the acidic condition triggers the disintegration of DFs, releasing the active Fe-G nanozymes with photothermally reinforced catalytic activity. Accordingly, colorimetric and photothermal dual-readout detection of tEVs is achieved with an ultrahigh sensitivity as low as 1.08 × 103 particles mL-1. Moreover, by integrating multiple aptamer-MB probes (targeting HER2, MUC1, and GPC3) with machine learning, a sensor array is constructed to classify different cancer types and distinguish liver cancer patients from those with hepatitis and healthy individuals, demonstrating the clinical potential of this assay for noninvasive diagnosis.