A Dual-Responsive CO-Releasing Nanoplatform Sensitizes Tumor Phototherapy via Glycolytic Intervention

Abstract Carbon monoxide (CO), as a glycolysis inhibitor, can reverse tumor resistance to therapy. However, uncontrolled release and the inadequacy of monotherapy often compromise therapeutic outcomes. Herein, we developed nanoplatforms (FCBON NPs) based on the photosensitizer (BON) and CO-delivering polymer (DSPE-PEG (FeCO)) to achieve synergistic photodynamic/photothermal/gas therapy (PDT/PTT/GT). FCBON NPs enable controlled CO release through a dual-responsive cascade mechanism including the activation by overexpressed hydrogen peroxide in the tumor and reactive oxygen species (ROS) generated during BON-mediated PDT. The released CO effectively inhibits glycolysis via GLUT1 suppression, leading to adenosine triphosphate (ATP) depletion and heat shock proteins (HSP70) downregulation, which sensitizes tumors to mild-temperature photothermal therapy (MTPTT) by attenuating their thermal resistance. In vitro and in vivo therapeutic results demonstrated that the synergistic PDT/PTT/GT achieves potent therapeutic effects compared to monotherapy. By demonstrating the power of CO-mediated metabolic intervention, this study provides a valuable framework for designing controlled gas-releasing nanoplatforms for enhanced multimodal cancer therapy.