Delivery System of Nanozymes Loaded with DNAzymes and Hypoxia‐Activated Prodrug for Anti‐Tumor Metastasis

Abstract Breast cancer is a common malignant tumor in women worldwide, and its high metastasis is the main reason for high mortality. Especially under hypoxic microenvironments, the upregulation of hypoxia‐inducible factor 1‐alpha (HIF‐1α) can activate the transcription factor Twist and promote tumor metastasis through epithelial‐mesenchymal transformation (EMT). Here, MnO ₂ nanosheets are synthesized with oxidase‐like activity using fucoidan as a protective agent, and construct a multifunctional delivery system MnO ₂ @DNAzyme‐TPZ (MDT) by loading DNAzymes and hypoxia‐activated prodrug Tirapazamine (TPZ) for tumor treatment and metastasis inhibition. MDT kills tumors by converting O ₂ into reactive oxygen species (ROS) through MnO ₂ nanozymes, and inhibits tumor metastasis by selectively silencing the tumor metastasis‐related Twist gene through DNAzymes. TPZ enhances tumor killing under hypoxic environments and synergistically inhibits tumor metastasis by reducing the expression of HIF‐1α. MDT significantly inhibits tumor growth and metastasis in vivo in an in situ tumor model. The strategy of combining selective gene silencing based on DNAzymes with nanozymes and hypoxia‐activated prodrug provides a new approach to anti‐tumor metastasis therapy.