Hydrogel delivering antifibrotic agent and nano-sonosensitizer enhances efficacy of sonodynamic therapy in osteosarcoma treatment

Sonodynamic therapy (SDT) is an emerging modality for cancer treatment that induces immunogenic cell death (ICD) through reactive oxygen species (ROS) generation, thereby triggering potent antitumor immunity. However, the hypoxic and glutathione (GSH)-rich tumor microenvironment restricts ROS production, while dense extracellular matrix (ECM) formed by cancer-associated fibroblasts (CAFs) further impedes immune cell infiltration. Here, we developed a hydrogel-based localized delivery platform co-encapsulating the nano-sonosensitizer PCN-224@MnO₂@HA (PMH), and SIS3, a SMAD3 inhibitor. Upon hydrogel-mediated local administration, MnO₂ catalyzes O₂ generation from endogenous hydrogen peroxide while depleting intracellular GSH, thereby amplifying ROS production during SDT. Concurrently, SIS3 reprograms CAFs by blocking TGF-β/SMAD3 signaling, reducing collagen deposition and promoting immune cell infiltration. In an osteosarcoma mouse model, the combination of PMH-mediated SDT with SIS3-induced CAF reprogramming reduced collagen deposition by approximately 50 % and triggered robust antitumor immune responses, which collectively contributed to a 76 % inhibition of tumor growth. Collectively, this study demonstrates a novel CAF-targeted SDT strategy integrating ECM remodeling, ROS enhancement, and localized delivery, offering a promising therapeutic paradigm for solid tumor treatment.