Ultrasound‐Triggered Peroxynitrite‐Mediated ECM Degradation to Enhance Sonodynamic Cancer Therapy

ABSTRACT The therapeutic efficacy against triple‐negative breast cancer (TNBC) is often limited by poor nanodrug penetration through the dense extracellular matrix (ECM). Although sonodynamic therapy (SDT) offers a non‐invasive approach with deep tissue penetration, its effectiveness using wide‐bandgap sonosensitizers is constrained by rapid electron‐hole recombination. Guided by AI‐driven screening, we developed narrow‐bandgap (1.0–1.5 eV) tin monosulfide (SnS) as a sonosensitizer, which was further engineered into a cascade reaction‐enhanced sonodynamic therapeutic system by loading nitric oxide (NO) donors and modifying with polyethylene glycol (PEG). Upon ultrasound stimulus, this system generates both ROS and NO, which not only exert the cytotoxic effects of sonodynamic therapy but also combine to yield highly cytotoxic peroxynitrite (ONOO − ). The resulting ONOO − activates matrix metalloproteinases (MMPs) to degrade the ECM, thereby enhancing nanoparticle penetration and establishing a self‐reinforcing antitumor cycle. Furthermore, this ultrasound‐driven strategy simultaneously induces mitochondrial apoptosis via ROS, overcoming the depth limitations of conventional light‐based therapies and presenting a potent approach for TNBC treatment.