Metabolic
rewiring, a dynamic metabolic phenotype switch, confers
that tumors exist and proliferate after fitness (or preadaptation)
in harsh environmental conditions. Glycolysis deprivation was considered
to be a tumor’s metabolic Achilles heel. However, metabolic
configuration can flexibly retune the mitochondrial metabolic ability
when glycolysis is scared, potentially resulting in more aggressive
clones. To address the challenge of mitochondrial reprogramming, an
antiglycolytic nanoparticle (GRPP NP) containing a novel mitochondrial-targeted
reactive oxygen species (ROS) generator (diIR780) was prepared to
hijack glucose and regulate mitochondria, thus completely eliminating
tumorigenic energy sources. In this process, GRPP NPs@diIR780 can
catalyze endogenous glucose, leading to significantly suppressed glycolysis.
Moreover, diIR780 can be released and selectively accumulated around
mitochondria to generate toxic ROS. These combined effects, in turn,
can hamper mitochondrial metabolism pathways, which are crucial for
driving tumor progression. This synchronous intervention strategy
enables utter devastation of metabolic rewiring, providing a promising
regiment to eradicate tumor lesions without recurrence.