Ultrasound‐Triggered Dinuclear Iridium Sonosensitizer Activates Paclitaxel Prodrug for Synergistic Sonodynamic‐Chemotherapy

Abstract Stimuli‐cleavable prodrug technology offers a promising strategy to mitigate the severe systemic toxicity associated with conventional chemotherapy. However, its clinical translation is hindered by insufficient and nonspecific activation within heterogeneous tumors. To address this challenge, an ultrasound (US)‐activated nanoplatform (PDTC@Ir/PTX 2 ‐TK NPs) that couples a binuclear iridium sonosensitizer (Ir‐DPP‐Ir) with a reactive oxygen species (ROS)‐responsive paclitaxel prodrug (PTX 2 ‐TK), encapsulated in a self‐crosslinked polycarbonate (PDTC) carrier, is constructed. The PDTC carrier, which contains 1,2‐dithiolane, promotes stability and prevents premature drug leakage. Ir‐DPP‐Ir functions as a potent sonosensitizer, generating multiple ROS (e.g., •OH, 1 O 2 , O 2 −· ) under therapeutic ultrasound. The PTX 2 ‐TK prodrug maintains pharmacologically inert in normal tissues but is highly sensitive to ROS, thereby avoiding off‐target effects and ensuring tumor‐specific activation. Upon US irradiation, over 99% of PTX 2 ‐TK is effectively activated, addressing the critical bottleneck of tumor‐specific prodrug activation. This synergistic sonodynamic‐chemotherapy strategy achieves potent tumor eradication (95.8% inhibition) and stimulates a robust anti‐tumor immune response, while significantly minimizing systemic toxicity associated with conventional PTX administration.