A pH/glutathione-dual-responsive drug-loaded heterostructure nanozyme for synergistic chemotherapy/chemodynamic therapy against melanoma.

Melanoma is an aggressive skin malignancy that originates from melanocytes. It remains a major clinical challenge because of its high drug resistance, frequent relapse, and metastatic potential. Although chemodynamic therapy (CDT) can selectively kill cancer cells by generating hydroxyl radicals (·OH) in the tumour microenvironment (TME), its efficacy is often limited by insufficient reactive oxygen species (ROS) production. In this study, we used a hyaluronic acid (HA)-modified Fe-based metal-organic framework (MOF) co-loaded with the chemotherapeutic drug norcantharidin (NCTD) and gold nanoparticles (AuNPs) to develop a pH/glutathione dual-responsive MOF-AuNPs-NCTD@HA (MAuN@HA) heterostructure nanozyme that amplifies ROS generation for synergistic chemotherapy/CDT against melanoma. Within the weakly acidic TME, the MAuN@HA dissociates, releasing iron ions and NCTD, enabling combined chemotherapy and Fe-mediated CDT. The integrated gold nanozyme executed cascade catalytic reactions, enabled by enhanced catalase-, peroxidase-, and oxidase-like activities along with the Russell effect, generating a burst of diverse ROS (including singlet oxygen, superoxide anion, and ·OH) and amplifying oxidative stress. Notably, HA modification conferred active tumour targeting. In a B16 tumour-bearing mouse model, the MAuN@HA heterostructure nanozyme potently suppressed melanoma progression. Overall, this study presented a TME-responsive nanozyme strategy that combined cascade catalysis with drug release to achieve an effective ROS-amplified synergistic therapy against melanoma.