Redox Imbalance Triggered Intratumoral Cascade Reaction for Tumor “turn on” Imaging and Synergistic Therapy

Abstract The redox homeostasis in tumors enhances their antioxidant defense ability, limiting reactive oxygen species mediated tumor therapy efficacy. The development of strategies for specific and continuous disruption of the redox homeostasis in tumor cells facilitates the improvement of the cancer therapeutic effect by promoting the apoptosis of tumor cells. Herein, a responsively biodegradable targeting multifunctional integrated nanosphere (HDMn‐QDs/PEG‐FA) is designed to enhance the anti‐tumor efficacy by triggering intratumoral cascade reactions to effectively disrupt intracellular redox homeostasis. Once HDMn‐QDs/PEG‐FA enters tumor cells, manganese dioxide (MnO₂) shell on the surface of nanosphere consumes glutathione (GSH) to produce Mn²⁺, enabling enhanced chemodynamic therapy (CDT) via a Fenton‐like reaction and T₁‐weighted magnetic resonance imaging. Meanwhile, the degradation of MnO₂ can also cause the fluorescence recovery of quantum dots conjugated on the surface of the shell, realizing “turn‐on” fluorescence imaging. In addition, the doxorubicin is released because of the cleavage of the embedded SS bond in the hybrid core framework by GSH. A superior synergistic therapeutic efficiency combined CDT and chemotherapy is shown by HDMn‐QDs/PEG‐FA in vivo. The tumor‐inhibition rate reaches to 94.8% and does not cause normal tissue damage due to the good targeting and tumor microenvironment‐specific response.