A Tumor Microenvironment-Responsive Self-Oxygenating Nanoplatform for Dual-Enhanced Cuproptosis and Sonodynamic Synergistic Immunotherapy

Hypoxia in the tumor microenvironment (TME) severely compromises the effectiveness of sonodynamic therapy (SDT) and disrupts the process of cuproptosis. SDT generates insufficient reactive oxygen species (ROS) under low oxygen levels, while cuproptosis is impeded by hypoxia-induced mitochondrial respiration suppression. To address these limitations, we develop a CaO₂-based self-oxygenating nanosonosensitizer incorporating a copper-based metal-organic framework (MOF) shell with loaded disulfiram (DSF), named CaO₂-MD, which undergoes TME-responsive disassembly to generate O₂ and release the drug. Upon ultrasound (US) irradiation, CaO₂-MD generates ROS via SDT and simultaneously triggers cuproptosis through the release of copper ions and DSF. <i>In vivo</i> and <i>in vitro</i> experiments indicate that CaO₂-MD can effectively alleviate tumor hypoxia, thereby synergistically activating cuproptosis and boosting SDT performance. In the 4T1 tumor model, CaO₂-MD with US irradiation achieves potent tumor suppression and a 40% cure rate which further increases to 80% when combination with PD-L1 blockade therapy. The durable immune memory is established to effectively prevent recurrence. This work breaks through the hypoxic TME limitations constraining both SDT and cuproptosis, offering a promising platform for developing effective cancer therapies based on TME reconstruction.