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

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.