Narrow-Bandgap Iridium(III)-C₃N₅ Nanocomplex as an Oxygen Self-Sufficient Piezo-Sonosensitizer for Hypoxic Tumor Sonodynamic Immunotherapy

Low immunogenicity and insufficient infiltration of immune cells are the main factors affecting the therapeutic efficacy of melanoma immunotherapy. Ultrasound-triggered sonodynamic therapy (SDT) based on piezoelectric materials has attracted substantial attention due to its high efficiency of piezoelectric catalytic generation of reactive oxygen species (ROS) to induce immunogenic cell death (ICD). However, the hypoxic environment in solid tumors hinders the infiltration of immune cells and limits the SDT effect. Herein, we construct a novel <b>Ir-C</b>_<b>3</b><b>N</b>_<b>5</b> nanocomplex that uses nitrogen-rich carbon nitride (C₃N₅) nanosheets as nanoligands and Ir(tpy)Cl₃ as a precursor. The newly formed <b>Ir-C</b>_<b>3</b><b>N</b>_<b>5</b> nanocomplex exhibits a narrowed band gap and an enlarged dipole moment, resulting in a better electron-hole pair separation and band bending, contributing to the ROS burst upon ultrasonic activation. In addition, Ir(III) enables the C₃N₅ nanosheets to catalyze the degradation of H₂O₂ to O₂, alleviating tumor hypoxia and reinforcing SDT efficacy. Mechanistically, due to the generation of ROS by piezoelectric catalysis, <b>Ir-C</b>_<b>3</b><b>N</b>_<b>5</b> can target lysosomes to trigger autophagy inhibition caused by lysosome rupture and to evoke pyroptosis. More importantly, the cleaved caspase-1/GSDMD-N pyroptosis pathway activated by <b>Ir-C</b>_<b>3</b><b>N</b>_<b>5</b> was associated with ICD, effectively initiating the innate and adaptive immunity of the body for suppressing tumor metastasis and relapse.