An Activatable Dual-Engine Metabolic Inhibition Switch: Sequential Blockade of Glycolysis and Mitochondrial Respiration Potentiates Photodynamic Therapy via Tumor Reoxygenation

Photodynamic therapy (PDT) is an emerging treatment modality that is progressively gaining popularity in clinical practice. Its attributes of minimal adverse effects and spatiotemporal selectivity instill hope among tumor patients. However, the hypoxic microenvironment within tumors significantly compromises the efficacy of PDT. Cuproptosis has recently emerged as a novel mode of cellular death by the disturbance of the tricarboxylic acid cycle. In this investigation, we demonstrated that the mechanism underlying cuproptosis can enhance the antitumor effect of PDT by throttling cellular oxygen consumption through mitochondrial respiration. The Warburg effect exhibited by tumor cells leads to a preferential utilization of glycolysis as the primary energy source, thereby significantly reducing the reliance on mitochondrial respiration. Herein, we developed a synergistic antitumor system by constructing a photosensitizer and copper supramolecular assembly loaded with glycolysis inhibitor galloflavin (GF) and coated with polydopamine. The obtained product GF/Cu-Pc@DA exhibited pH- and protein-cascaded responsive drug release, along with switchable fluorescence and photodynamic activity, and can lead to a significant enhancement in intracellular oxygen levels to promote the generation of photodynamic reactive oxygen species (ROS), disrupt mitochondrial respiration, and inhibit glycolytic metabolism. Moreover, both in vivo and in vitro studies demonstrated the excellent synergistic antitumor effect of GF/Cu-Pc@DA with no significant side effects. This study presents novel perspectives for the development of highly effective photodynamic antitumor therapy strategies, contributing valuable guidance for further advancements in clinical PDT.