Organic Sonosensitizers-based SDT with enhanced ROS generation

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 O₂-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 O₂-delivery/generation tumor reoxygenation approaches for enhanced SDT, such as O₂-nanocarriers, in-situ catalytic O₂ generation, and mitochondrial respiration modulation etc. Notably, integrating clinically validated sonosensitizers like porphyrins with translational O₂-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.