Intraperitoneal Copper–Manganese Nanozyme Suppresses Peritoneal Metastasis with Antitumor Immune Activation

Abstract

Peritoneal metastasis from colorectal cancer (CRC) carries a dismal prognosis, and current surgical and medical therapies achieve limited efficacy with high recurrence rates. Here, we developed a copper–manganese-based nanozyme (CM) that integrated MnO2-mediated Fenton-like catalysis with copper-induced cuproptosis for intraperitoneal treatment of CRC peritoneal metastasis. Composed of CuO and Cu2(OH)3Cl crystalline domains embedded in amorphous MnO2, the nanozyme has a hydrodynamic diameter of ~140 nm and displays peroxidase-like, glutathione oxidase, catalase, and Fenton-like activities that amplify reactive oxygen species (ROS) under tumor-mimicking conditions. CRC cells efficiently internalize the nanozyme, which penetrates 3-dimensional spheroids and induces strong, selective cytotoxicity via ROS amplification and cuproptosis. Intraperitoneal delivery of CM achieves prolonged peritoneal retention, marked reduction of peritoneal tumor burden and ascites, and remodeling of the local immune microenvironment with activation of antitumor immune responses. This study provides an effective cavity-confined therapeutic approach for CRC peritoneal metastasis based on Fenton-like ROS amplification and cuproptosis.