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

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.