Dual‐Enhanced Sonodynamic Therapy: Synergizing Cavitation Amplification and Efficient Sonoluminescence‐to‐ROS Conversion for Orthotopic Breast Cancer Treatment

Abstract Sonodynamic therapy (SDT), as a promising noninvasive therapeutic modality with superior penetration depth, receives tremendous attention. To date, the widely accepted mechanism for reactive oxygen species (ROS) generation in SDT involves acoustic cavitation‐triggered sonoluminescence (SL), followed by the SL‐activation of sonosensitizers. However, current research on sonosensitizer development primarily focuses on promoting SL‐to‐ROS conversion, overlooking the essential role of the cavitation process. To fully unleash the potential of SDT, herein, a dual‐enhanced strategy that harnesses the enhanced cavitation for SL generation and efficient SL‐to‐ROS conversion is developed for the first time to realize an all‐around enhancement of SDT. Specifically, the proposed nano‐sonosensitizer, namely MeTTh‐PAE NPs, is released as hydrophobic aggregates with a rough surface in response to an acidic environment, allowing for highly enhanced cavitation‐triggered SL under ultrasound. Meanwhile, as a typical aggregation‐induced emission molecule, MeTTh demonstrates a highly promoted intersystem crossing process at its aggregated state, facilitating efficient SL‐to‐ROS conversion. Notably, combining these two fascinating attributes in MeTTh‐PAE NPs results in an excellent sonodynamic antitumor effect in both in vitro and in vivo. This work proposes a novel strategy to fully exploit the potential of SDT and provides valuable insights for advancing the design of nano‐sonosensitizers.