Acid-responsive cobalt-doped ZIF-8 nanoplatform potentiates ferroptosis in osteosarcoma by disrupting the PSMD14/SLC7A11 axis.

Ferroptosis induction represents a promising antitumor strategy, yet osteosarcoma cells frequently resist ferroptosis through the PSMD14-mediated stabilization of SLC7A11. Here, we report an acid-responsive cobalt-doped ZIF-8 nanoplatform loaded with 1, 10-phenanthroline and coated with PEG (denoted as CPP) that simultaneously amplifies oxidative stress and dismantles the PSMD14/SLC7A11 antioxidant axis. Upon exposure to the acidic tumor microenvironment, the ZIF-8 framework degrades, releasing Co2+ ions that catalyze Fenton-like reactions to generate hydroxyl radicals (•OH) and initiate lipid peroxidation. Concurrently, 1, 10-phenanthroline chelates the catalytic Zn2+ of PSMD14, abolishing its deubiquitinase activity and thereby promoting ubiquitin-dependent degradation of SLC7A11, which depletes intracellular glutathione (GSH). Physicochemical characterization confirmed the successful construction of CPP nanoparticles (~100 nm) with a drug loading efficiency of 14.76% and pH-triggered Co2+ release. In vitro, CPP was efficiently internalized by 143B osteosarcoma cells and exhibited dose-dependent cytotoxicity with markedly elevated reactive oxygen species (ROS), malondialdehyde (MDA) accumulation, lipid peroxidation, mitochondrial depolarization, and downregulation of SLC7A11 and GPX4, collectively supporting ferroptosis. CPP also significantly suppressed osteosarcoma cell invasion. In a subcutaneous 143B xenograft model, intravenous CPP administration reduced tumor volume by approximately 80% relative to controls, with pronounced tumor necrosis, proliferation inhibition, and decreased SLC7A11/GPX4 expression in tumor tissues, while maintaining favorable biosafety. These findings establish CPP as a dual-action nanoplatform for ferroptosis-based osteosarcoma therapy.