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

Abstract 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 H ₂ O ₂ 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.