Beyond Catalytic Therapy: Copper‐Paeonol Nanozymes Disrupt Fascin‐Mediated Actin Bundling to Suppress Tumor Growth and Metastasis

Fascin, an actin-bundling protein universally upregulated in metastatic tumors, drives tumor migration and invasion by promoting filopodia and invadopodia formation, establishing it as a pivotal therapeutic target. Herein, copper-paeonol nanozymes (CuPaeNs) is engineered through metal-phenolic complexation, mimicking natural enzyme metal-coordination microenvironments to confer peroxidase-like activity. This enzymatic capability drives the conversion of tumor-associated H₂O₂ into cytotoxic hydroxyl radicals, inducing oxidative damage in malignant cells. Notably, beyond inducing tumor catalytic therapy via targeted ROS generation, CuPaeNs directly disrupted the actin-bundling activity of fascin, as evidenced by molecular docking, isothermal titration calorimetry, co-immunoprecipitation, and immunofluorescence assays. Transcriptomic and biochemical analyses further revealed that CuPaeNs suppressed melanoma glycolysis by blocking the fascin-YAP1-PFKFB3 signaling axis. This study establishes metal-phenolic nanozymes as a dual-functional strategy that simultaneously triggers ROS overproduction to amplify tumor oxidative stress and disrupts fascin-mediated metastasis, thereby modulating tumor metabolic reprogramming. This coordinated intervention establishes a novel treatment framework for malignancies characterized by fascin overexpression.