Copper-Based Metal-Polyphenol Network Encapsulated Mesoporous Silica for Targeted Cuproptosis Induction and Immunotherapy in Melanoma

Melanoma is a malignant neoplasm of the skin, distinguished by its high invasiveness and propensity for metastasis, thereby posing substantial challenges for therapeutic intervention. Here, we developed a metal-polyphenol network (MPN)- based drug delivery system (GD@MSN-CG) that induced cuproptosis and enhanced immunotherapy efficacy, thereby inhibiting melanoma progression and reducing the risk of metastasis. In the system, mesoporous silica nanoparticles (MSN) loaded with doxorubicin (DOX) and glucose oxidase (GOx) are surface-coated with Cu-based MPN (CuGA) to form GD@MSN-CG. After internalization by melanoma cells, copper ions, DOX, and GOx would be released, consuming glucose and glutathione, and producing substantial H 2 O 2, which further induces strong cuproptosis. Cuproptosis in melanoma cells triggered Immunogenic cell death (ICD). In vivo and in vitro assessments demonstrated that GD@MSN-CG effectively induced cuproptosis, activated antitumor immune response, and improved treatment effect. Copper-based MPN coating on GD@MSN-CG reduced systemic toxicity and showed strong therapeutic effectiveness, indicating its promise as a carrier modification for cancer treatments.