Charge-Reversal Near-Infrared II Polymeric Amphiphiles Enable Efficient Combinatorial Gene and Mild Photothermal Therapy for Osteosarcoma

Osteosarcoma (OS) presents formidable challenges due to its aggressive progression and resistance to conventional therapies. Recent advancements in multimodal strategies, such as combining gene therapy with mild-temperature photothermal therapy (mPTT), referred to as GT-mPTT, have shown promise in enhancing therapeutic efficacy while minimizing side effects. However, current systems face limitations in therapeutic response, efficiency, and biosafety. Herein, we report a reactive oxygen species (ROS)-responsive polymeric amphiphile for imaging-guided combinational GT-mPTT therapy, achieving a high-efficiency antitumor performance against OS. This polymer incorporates guanidine-functionalized units for effective gene condensation and near-infrared II (NIR-II) active dyes for efficient photothermal conversion. The system exhibits charge reversal under elevated intratumoral ROS levels, promoting gene release, and achieves controlled mild hyperthermia under NIR-II irradiation, enhancing cellular uptake and enabling effective mPTT. The GT-mPTT combination therapy, guided by dual NIR-II fluorescence and photothermal imaging, demonstrated significant therapeutic outcomes in vitro and in vivo. These include pronounced tumor cell apoptosis, substantial tumor size reduction, and mitigation of osteolysis in OS-bearing mouse models, all while maintaining excellent biosafety and negligible systemic toxicity. This work shows the potential of responsive polymeric platforms with integrated multimodal therapeutic and imaging capabilities as a robust foundation for advancing precision therapies against OS.