A Lysosome-Targeted Iridium(III) Complex Inducing Pyroptosis for Enhanced Sonodynamic Therapy of Colorectal Cancer

Sonodynamic therapy (SDT) is a promising noninvasive cancer treatment due to its superior tissue penetration depth compared to phototherapy. Herein, we developed a lysosome-targeted cyclometalated Ir(III) complex (<b>Lyso-Ir</b>) as a highly efficient sonosensitizer and sonoredox catalyst for enhanced SDT against colorectal cancer. <b>Lyso-Ir</b> outperforms [Ru(bpy)₃]Cl₂ in both ¹O₂ generation (2.74-fold) and sonocatalytic oxidation of NADH (2.92-fold). Notably, under lysosomal pH conditions, its performance is significantly enhanced with improvements of 22.9-fold (¹O₂ generation) and 7.5-fold (NADH oxidation) over neutral physiological conditions, respectively. This is advantageous for tumor therapy, given the inherent weak acidity of lysosomes and the tumor microenvironment. Notably, <b>Lyso-Ir</b> could target the lysosome, generate ¹O₂ under ultrasound irradiation, induce lysosomal membrane permeabilization, activate caspase-3, trigger GSDME cleavage, and ultimately lead to pyroptosis. This is highly advantageous for overcoming apoptosis resistance and activating antitumor immune responses. This work provides a promising new strategy for the treatment of deep-seated colorectal tumors.