Copper-Based Responsive Nanoplatform for Synergistic Chemodynamic and Photodynamic Treatment of Osteosarcoma

Osteosarcoma (OS) remains a highly aggressive malignancy in adolescents, characterized by rapid metastasis, poor prognosis, and limited response to conventional treatments such as surgery and chemotherapy, largely due to low specificity, severe side effects, and insufficient control of metastatic lesions. The tumor microenvironment (TME) of OS features high GSH levels and elevated oxidative stress, making it particularly susceptible to redox-based therapies. Strategies that amplify reactive oxygen species (ROS), such as chemodynamic therapy (CDT) and photodynamic therapy (PDT), offer selective tumor destruction and overcome conventional treatment limitations. Herein, we report a copper-based metal–organic framework (MOF) nanoplatform, Cu2O@CuHHTP@ZnPc@HA (CCHZH), featuring a hierarchical core–shell architecture and glutathione (GSH)-responsive degradability, and active OS-targeting capability. The nanoparticles exhibited a uniform hollow spherical structure with an average diameter of approximately 200 nm. Leveraging both passive targeting via the enhanced permeability and retention (EPR) effect with active targeting through hyaluronic acid (HA)–CD44 interaction, the nanoparticles accumulate selectively at OS sites, subsequently undergoing GSH-triggered disassembly to release Cu+ ions and the photosensitizer ZnPc. The liberated Cu+ initiates Fenton-like reactions, generating cytotoxic hydroxyl radicals (•OH) for CDT, while ZnPc produces singlet oxygen (1O2) under 670 nm laser irradiation for PDT. This dual-modal reactive oxygen species (ROS) production synergistically disrupts cellular redox homeostasis, markedly enhancing oxidative stress. Mechanistically, CCHZH with 670 nm laser irradiation activates mitochondrial apoptosis via the Bax/Bcl-2/Caspase-3 signaling axis and simultaneously induces cuproptosis through suppression of FDX1 and LIAS expression. In vitro, CCHZH reduced cell viability to 10% and induced 80% late apoptosis, as confirmed by flow cytometry. Consistently, in vivo evaluations demonstrated potent therapeutic efficacy and safety in subcutaneous, orthotopic, and lung metastasis osteosarcoma models. Collectively, our study introduces a targeted, redox-responsive nanoplatform with robust CDT/PDT synergy and dual-pathway cell death induction, providing a safe and effective therapeutic approach for OS.