Sono-dynamic therapy (SDT) is an emerging cancer treatment approach that induces immunogenic cell death (ICD) through the generation of reactive oxygen species (ROS), thereby triggering effective anti-tumor immunity. However, hypoxia and the glutathione-rich tumor microenvironment limit the production of ROS, while the dense extracellular matrix (ECM) formed by cancer-associated fibroblasts (CAF) further hinders the infiltration of immune cells. Here, we have developed a local delivery platform based on hydrogels, which encapsulates the nanosound sensitizer PCN-224@MnO2@HA (PMH) and SIS3 (a SMAD3 inhibitor) together. In hydrogel-mediated local administration, MnO2 catalyzes the production of O2 from endogenous hydrogen peroxide and consumes intracellular GSH, thereby amplifying ROS production during SDT. Meanwhile, SIS3 reprograms CAF by blocking TGF-β/SMAD3 signaling, reducing collagen deposition, and promoting immune cell infiltration. In a mouse model of osteosarcoma, PMH-mediated SDT combined with CAF reprogramming induced by SIS3 can reduce collagen deposition by approximately 50% and trigger a strong anti-tumor immune response, jointly contributing to the inhibition of 76% tumor growth. In summary, this study demonstrates a new CAF-targeted SDT strategy that integrates ECM remodeling, ROS enhancement, and local delivery, providing a promising treatment paradigm for solid tumor therapy. This study was published in Bioactive Materials under the title "Hydrogel delivering antifibrotic agent and nano-sonosensitizer enhances the efficacy of sonodynamic therapy in osteosarcoma treatment".
Reference News: 
DOI: 10.1016/j.bioactmat.2025.10.001