Organic sonosensitizers for cancer therapy: molecular engineering from band-gap control to clinical application

Sonodynamic therapy (SDT) has emerged as a promising non-invasive cancer treatment. By employing low-intensity focused ultrasound, SDT activates sonosensitizers to produce cytotoxic reactive oxygen species (ROS), enabling selective tumor cell death at tissue depths exceeding 10 cm. Due to their excellent safety profiles, structural tunability, biodegradability, and ease of rational synthetic modification, organic small molecules have increasingly surpassed their inorganic counterparts as the preferred class of sonosensitizers. This review provides a comprehensive, family-by-family analysis of organic sonosensitizers, encompassing porphyrins, phthalocyanines, BODIPY derivatives, xanthenes, cyanines, aggregation-induced emission luminogens (AIEgens), boron-doped acene compounds, and natural product-derived sensitizers. We methodically examine the molecular underpinnings of SDT, including ultrasonic cavitation, sonoluminescence, pyrolysis, and band gap-mediated ROS generation via Type I and Type II pathways. Furthermore, we critically evaluate the key structure-activity relationships (SARs) governing sonosensitizing performance across these compound families, specifically highlighting HOMO-LUMO gap engineering, intersystem crossing (ISC) efficiency, heavy atom effects, donor-acceptor designs, and aggregation behaviors. Beyond molecular design, this review assesses nanotechnological delivery strategies engineered to overcome tumor hypoxia, enable stimuli-responsive activation, and achieve precise immunological reprogramming of the tumor microenvironment. Finally, we evaluate available clinical data on porphyrin- and chlorin-based sensitizers alongside their inherent structural limitations. Ultimately, this review seeks to bridge the gap between academic innovation and clinical translation, offering a foundational reference for the next generation of acoustically activated cancer therapeutics.