Synergetic lethal energy depletion initiated by cancer cell membrane camouflaged nano-inhibitor for cancer therapy

Mitochondrial bioenergy plays a vital role in the occurrence and development of cancer. Although strategies to impede mitochondrial energy supply have been rapidly developed, the anticancer efficacy is still far from satisfactory, mainly attributed to the hybrid metabolic pathways of mitochondrial oxidative phosphorylation (OXPHOS) and glycolysis. Herein, we construct a cancer cell membrane camouflaged nano-inhibitor, mTPPa–Sy nanoparticle (NP), which co-encapsulates OXPHOS inhibitor (mitochondrial-targeting photosensitizers: TPPa) and glycolysis inhibitor (syrosingopine (Sy)) for synergistically blocking the two different energy pathways. The mTPPa–Sy NPs exhibit precision tumor-targeting due to the high affinity between the biomimic membrane and the homotypic cancer cells. Under laser irradiation, the mitochondrial-targeting TPPa, which is synthesized by conjugating pyropheophorbide a (PPa) with triphenylphosphin, produces excessive reactive oxygen species (ROS) and further disrupts the OXPHOS. Interestingly, OXPHOS inhibition reduces O₂ consumption and improves ROS production, further constructing a closed-loop OXPHOS inhibition system. Moreover, TPPa-initiated OXPHOS inhibition in combination with the Sy-triggered glycolysis inhibition results in lethal energy depletion, significantly suppressing tumor growth even after a single treatment. Our findings highlight the necessity and effectiveness of synergetic lethal energy depletion, providing a prospective strategy for efficient cancer therapy.