Outwitting the Hypoxic Fortress: Self-Assembled Glucose-Powered Mitochondria-Targeting Ru Nanoassemblies for Triad...

Conventional sonodynamic therapy (SDT) is limited by the immunosuppressive tumor microenvironment (TME), characterized by hypoxia and potent antioxidant defenses. To address these challenges, we developed RGH@TK-FA, a nanoplatform codelivering a mitochondria-targeting ruthenium sonosensitizer (RuSS), glucose oxidase (GOx), and hemoglobin (Hb), encapsulated within a PEG shell modified with folate and ROS-responsive linkers. Under ultrasound, RuSS generates ROS via type I and II mechanisms while depleting cellular reductants. The resulting ROS trigger cargo release, initiating a self-amplifying cascade: GOx consumes glucose and oxygen to produce H₂O₂ and acidify the TME, while Hb supplies O₂ and acts as a Fenton-like catalyst for chemodynamic therapy. ROS also promote iron release from Hb, establishing a self-sustaining feedback loop that intensifies oxidative stress. This ROS storm disrupts redox homeostasis and induces immunogenic cell death via ferroptosis, reprogramming the immunosuppressive TME. This work overcomes SDT limitations through a self-reinforcing multimodal therapeutic cycle for precision cancer treatment.