Overcoming phototoxicity of sonosensitizers: Curcumin-coordinated iridium(III) complexes for sonodynamic therapy

Sonodynamic therapy (SDT) holds promise for deep-seated tumors, but most sonosensitizers suffer from severe phototoxicity, requiring patients to avoid light exposure after treatment. Here, we introduce a strategy using natural product curcumin as an auxiliary ligand to construct iridium(III) complexes (Ir1-Ir3). Ir3, featuring dual natural-product-derived ligands (curcumin and coumarin 6), exhibits a well-separated HOMO-LUMO distribution and a small S₁-T₁ energy gap, enabling highly efficient ultrasound (US)-triggered singlet oxygen (¹O₂) generation while showing negligible phototoxicity under light irradiation. Encapsulated with DSPE-PEG₂₀₀₀, Ir3 NPs are efficiently taken up by cancer cells and produce potent ¹O₂ upon US exposure, inducing immunogenic cell death. In a 4 T1 breast tumor model, Ir3 NPs + US significantly suppress tumor growth and lung metastasis by promoting dendritic cell maturation and CD8⁺ T cell infiltration. Remarkably, the sonodynamic efficacy persists through 6 cm of tissue-mimicking barrier, and contralateral US irradiation in vivo still achieves deep tumor suppression. This work establishes a natural-product-coordinated metal complex as a high-performance, low-phototoxicity sonosensitizer, overcoming a major clinical barrier of SDT and enabling deep-tissue cancer immunotherapy.