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 Ir-C3N5 nanocomplex that uses nitrogen-rich carbon nitride (C3N5) nanosheets as nanoligands and Ir(tpy)Cl3 as a precursor. The newly formed Ir-C3N5 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, Ir-C3N5 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 Ir-C3N5 was associated with ICD, effectively initiating the innate and adaptive immunity of the body for suppressing tumor metastasis and relapse.