Two-Dimensional Iridium(III)–Carbon Nitride Nanocomplexes Induce Simultaneous Oncosis and Necroptosis for Synergistic Chemo- and Sono-Immunotherapy in Hypoxic Melanoma

Hypoxic solid tumors present significant obstacles to cancer immunotherapy, primarily due to inadequate reactive oxygen species (ROS) production and profound immunosuppression. In this study, we rationally designed two Ir(III)-carbon nitride nanocomplexes, <b>Ir</b>_<b>309</b>-<b>C</b>_<b>3</b><b>N</b>_<b>5</b> and <b>Ir</b>_<b>443</b>-<b>C</b>_<b>3</b><b>N</b>_<b>5</b>, fabricated using Ir(III) polypyridine complexes as precursors and C₃N₅ nanosheets as nanoligands. Notably, benzothiazole modification of <b>Ir</b>_<b>443</b>-<b>C</b>_<b>3</b><b>N</b>_<b>5</b> imparted ultrasound-independent chemotherapeutic activity via ligand design, enabling the induction of oncosis even without ultrasound (US) stimulation. This modification simultaneously narrowed the bandgap, increased the dipole moment and piezoelectric coefficient, and stabilized metal-to-ligand charge transfer (MLCT) states, thereby extending charge-separated state lifetimes and enhancing ROS generation. Under US irradiation, <b>Ir</b>_<b>443</b>-<b>C</b>_<b>3</b><b>N</b>_<b>5</b> demonstrated superior self-sufficient oxygen supply and ROS production efficiency, leading to effective carrier utilization. Mechanistically, <b>Ir</b>_<b>443</b>-<b>C</b>_<b>3</b><b>N</b>_<b>5</b>@PEG selectively accumulated in mitochondria and the endoplasmic reticulum (ER), inducing ER stress and triggering oncosis, while US activation amplified oxidative stress to initiate necroptosis. The concurrent induction of oncosis and necroptosis fostered robust immunogenic cell death (ICD), dendritic cell maturation, macrophage polarization, and cytotoxic T-cell activation. As a result, this two-dimensional Ir(III)-based nanoplatform synergistically combines chemo- and sono-immunotherapy to overcome hypoxia and immunosuppression, effectively suppressing tumor metastasis and recurrence in melanoma-bearing mice.