Drug repurposing: isosorbide mononitrate enhances tumor accumulation to augment sonodynamic therapy for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) remains a leading cause of cancer death worldwide. Sonodynamic therapy (SDT) offers a non-invasive, deep-penetrating approach by using ultrasound to activate sonosensitizers and generate cytotoxic reactive oxygen species (ROS). Yet poor intratumoral delivery and low ROS quantum yields of existing agents have stalled clinical translation. Here, we present a synergistic SDT platform that overcomes these barriers by combining transient vasodilation of tumor microvessels with the clinically widely used Antianginal drug isosorbide mononitrate and an acceptor-donor-acceptor-donor-acceptor type organic nanosonosensitizer (BTz) engineered for a narrow bandgap and enhanced ultrasound responsiveness. Isosorbide mononitrate increases nanosonosensitizer accumulation by ~ 1.8-fold. Under ultrasound irradiation, nanosonosensitizer produced high ROS generation, resulting in 78% tumor growth inhibition in murine HCC models-nearly double that of SDT alone-without detectable systemic toxicity. Crucially, the near-infrared fluorescence of nanosonosensitizer enabled real-time, image-guided tracking of sonosensitizer uptake and therapeutic response. By repurposing a safe vasodilator and integrating it with a high-performance organic sonosensitizer, this work establishes a readily translatable, minimally invasive paradigm for precise SDT of localized, inoperable or metastatic HCC.