Tumor-Microenvironment-Activated DOX@Cu2S@PDA@MnO2 Nanoplatform for MRI/PAI-Assisted Chemophotothermal Therapy of...

Osteosarcoma remains difficult to treat because surgery and chemotherapy can provide incomplete tumor control, cause systemic toxicity, and lack reliable local monitoring. In this study, a tumor-microenvironment-activated DOX@Cu2S@PDA@MnO2 nanoplatform was prepared by converting Cu2O nanocubes into hollow Cu2S, coating polydopamine, growing a MnO2 shell, and loading doxorubicin. The Cu2S/PDA structure enabled strong NIR absorption and drug loading, while MnO2 responded to acidic H2O2/GSH-rich conditions to promote O2 generation, ROS-related reactions, and enhanced T1 MRI contrast. The nanoplatform showed concentration-dependent photothermal conversion at 808 and 1024 nm, microenvironment-responsive DOX release, increased intracellular ROS, and stronger killing of 143B osteosarcoma cells under NIR irradiation than carrier or free-drug controls. In tumor-bearing mice, it enhanced MRI/photoacoustic signals, enabled local photothermal heating, markedly inhibited tumor growth, and increased H&E-defined tumor damage and TUNEL-positive apoptosis, especially with 1024 nm irradiation. Hemolysis, organ histology, hematology, and blood biochemistry indicated acceptable short-term safety after repeated intratumoral administration. These results support this Cu2S/PDA/MnO2-based platform for imaging-guided localized osteosarcoma therapy.