One-Step Integration of Tumor Microenvironment-Responsive Calcium and Copper Peroxides Nanocomposite for Enhanced Chemodynamic/Ion-Interference Therapy

Recently, various metal peroxide nanomaterials have drawn increasing attention as an efficient hydrogen peroxide (H₂O₂) self-supplying agent for enhanced tumor therapy. However, a single kind of metal peroxide is insufficient to achieve more effective antitumor performance. Here, a hyaluronic acid modified calcium and copper peroxides nanocomposite has been synthesized by a simple one-step strategy. After effective accumulation at the tumor site due to the enhanced permeability and retention (EPR) effect and specific recognition of hyaluronate acid with CD44 protein on the surface of tumor cells, plenty of Ca²⁺, Cu²⁺, and H₂O₂ can be simultaneously released in acid and hyaluronidase overexpressed tumor microenvironment (TME), generating abundant hydroxyl radical through enhanced Fenton-type reaction between Cu²⁺ and self-supplying H₂O₂ with the assistance of glutathione depletion. Overloaded Ca²⁺ can lead to mitochondria injury and thus enhance the oxidative stress in tumor cells. Moreover, an unbalanced calcium transport channel caused by oxidative stress can further promote tumor calcification and necrosis, which is generally defined as ion-interference therapy. As a result, the synergistic effect of Fenton-like reaction by Cu²⁺ and mitochondria dysfunction by Ca²⁺ in ROS generation is performed. Therefore, a TME-responsive calcium and copper peroxides nanocomposite based on one-step integration has been successfully established and exhibits a more satisfactory antitumor efficiency than any single kind of metal peroxide.