Zn/Cu Bi‐Single‐Atom Nanoplatform: Hexagonal Anti‐Tumor Warrior by ROS Amplification for DOX Resistance Reversal and Immune Activation

Abstract Severe resistance of doxorubicin (DOX) caused by drug efflux and immunosuppression has led to a high treatment failure risk of breast cancer (BC). Compared with the single atom nanozymes, the bi‐single‐atomic nanozymes obtained through sequential single‐atom synthesis strategy in different spaces of the same nanomaterial, can significantly improve the space utilization efficiency and catalytic capacity. In this study, bi‐single‐atom nanozymes (Zn/Cu‐BSAN‐DOX NPs) are designed to reverse BC DOX resistance by causing damage to mitochondria of mesenchymal stem cells (MSCs) and 4T1 cells through reactive oxygen species (ROS) amplification. In situ H 2 O 2 self‐supply is improved by releasing DOX through activating the nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs). ROS amplification is triggered by enhanced chemodynamic therapy (CDT) and sonodynamic therapy (SDT) of Zn/Cu‐BSAN, which efficiently reverses the DOX resistance by breaking the hyaluronic acid (HA) barrier and DOX efflux. Furthermore, ROS amplification significantly promotes the immune improvement including DCs maturation, T cell activation, and the polarization of M1 macrophage. In summary, as “hexagonal” anti‐tumor warrior, Zn/Cu‐BSAN‐DOX NPs show great potential for multimodal DOX‐resistant BC therapy, which further expands the new preparation strategy and the clinical anti‐tumor application paradigm of single‐atom nanozymes.