Electron-Shuttling Mechanisms Drive Proximity Labeling to Unveil Tumor Marker Characteristics in Ovarian Cancer from Clinical Samples

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In this study, we presented a revolutionary proximity labeling platform, MOF-HRP-Apt, which for the first time integrated electron mediation into the horseradish peroxidase (HRP)-catalyzed proximity labeling system. This novel strategy enabled a single molecular recognition event into multiple covalent labeling events, amplifying spatial signals and enhancing detection sensitivity of the tumor biomarker PTK7. The platform utilized the redox-active iron-based metal–organic framework (MOF) material NH 2 -MIL-88B, whose Fe 2+ /Fe 3+ redox center facilitated electron transfer to the active site of HRP, dramatically boosting HRP’s catalytic activity toward phenol oxidation and accelerating phenoxo radical generation. These radicals could covalently label tyrosine residues in PTK7 and its adjacent proteins to achieve efficient spatial localization. Compared to conventional HRP-Apt strategies, MOF-HRP-Apt platform exhibited significantly stronger labeling signals (1.74-3 folds increase) and improved signal-to-noise ratios (1.93−2.2 folds enhancement) in cellular models. It maintained robust performance even under challenging conditions of low PTK7 expression, siRNA-mediated knockdown, or paclitaxel-induced suppression. Moreover, in clinical tissue specimens, our platform successfully enabled stratified PTK7 visualization across the ovarian cancer progression spectrum─from normal tissue through early to advanced stages, demonstrating its exceptional sensitivity and adaptability in complex biological environments. By combining target-specific recognition with signal amplification, this strategy offered the ultrasensitive detection of low-abundance biomarkers. With its remarkable potential for early cancer screening, real-time molecular tracking, and personalized therapeutic development, our platform represents a significant leap forward in molecular diagnostics. This study exemplifies the transformative power of electron-mediated proximity labeling, offering a promising avenue for advancing precision medicine and molecular biology.

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