Qianyun Shan, Rumei Li, Bin Ying, Wei Zhu, Xiaojin Wu, Shouxing Xu, Xuanxuan Zhang, Zhikang Xu, Xinyue Zhu, Weiyu Chen, Kai Zhang, Jian Chen
Organic sonosensitizer-based sonodynamic therapy (SDT) is an emerging, non-invasive strategy for cancer treatment, leveraging ultrasound (US) activation to trigger reactive oxygen species (ROS) production and induce tumor cell apoptosis. However, the clinical translation of SDT is limited by two key factors: the intrinsically low ROS quantum yield of many organic sonosensitizers and the hypoxic tumor microenvironment (TME), which restricts O 2 -dependent ROS generation. This review systematically examines recent molecular design strategies aimed at enhancing ROS production, including heavy atom incorporation, donor–acceptor (D-A) architecture design, π-conjugation extension, and solubility modulation. Furthermore, we evaluated innovative O 2 -delivery/generation tumor reoxygenation approaches for enhanced SDT, such as O 2 -nanocarriers, in-situ catalytic O 2 generation, and mitochondrial respiration modulation etc. Notably, integrating clinically validated sonosensitizers like porphyrins with translational O 2 -delivery systems such as perfluorocarbon (PFC) nanoemulsions or vascular normalization, offers a synergistic strategy to overcome tumor hypoxia, amplify ROS generation, and unlock the full therapeutic potential of SDT in future clinical applications.