Rare-Earth-Coordinated Glutamine Nanostructure-Induced “Pseudo-Overnutrition” Metabolic Therapy

Here, we propose a metabolic therapeutic strategy that leverages rather than suppresses tumor nutrient addiction, termed “pseudo-overnutrition”. This approach induces tumor cells to continuously uptake nutrient analogs that cannot be effectively utilized, thereby decoupling nutrient input from nutrient utilization and triggering metabolic collapse.

To validate this concept, we designed and assembled rare-earth–coordinated glutamine nanoparticles (RE-Gln). RE-Gln preferentially interacts with glutamine transporters on tumor-cell membranes, is subsequently internalized predominantly through macropinocytosis, and accumulates within lysosomes. The progressive accumulation of RE-Gln disrupts V-ATPase–dependent lysosomal nutrient sensing and blocks mTORC1 activation, rendering cells unable to effectively utilize nutrients despite continuous uptake.