A Novel Narrow Bandgap Ru-Doped Sonosensitive Nanosystem with Mitochondrial Targeting/Ultrasound-Responsive CO Release for Tumor Therapy

Cell organelle-based tumor-targeting strategies offer more precise approaches for tumor treatment, reducing adverse reactions and drug dosage. Mitochondria play a crucial role in cell proliferation and signal transduction, making them important organelle targets for disease intervention. This study developed a novel mitochondria-targeting and ultrasound-responsive nanosystem (MRTP) that can control the release of reactive oxygen species (ROS) and carbon monoxide (CO). MRTP is a combination of narrow-band gap sonosensitizers and mitochondria-targeting CO-releasing molecules. It can effectively cross both cellular and mitochondrial barriers and selectively target tumor cell mitochondria. When ultrasound is focused on the tumor site, MRTP can precisely release ROS and CO. Interestingly, MRTP can improve the tumor microenvironment (TME), not only alleviating tumor hypoxia but also depleting glutathione and catalyzing the generation of ^·OH from H₂O₂. These TME regulatory strategies can increase the level of ROS production. Ultimately, the cascade effect of ROS and CO generation will reduce mitochondrial membrane potential, promote tumor cell apoptosis, and inhibit tumor growth.