We proposed a cascade metabolic blockade strategy to overcome adaptive metabolic compensation in PDAC starvation therapy. A hypoxia-responsive nanomedicine was designed for self-amplified delivery of glucose oxidase (GOx) to consume glucose and chloroquine (CQ) to inhibit lysosome-mediated metabolic compensation. Combined with a biomimetic tumor-targeting carrier, this system disrupts metabolic plasticity, amplifies bioenergetic stress, and provides a translatable framework for glycolysis-addicted malignancies.

Summary

This study reports a novel self-amplifying nanomedicine CM@GOx/HRP/CQ for pancreatic ductal adenocarcinoma (PDAC). The drug uses homologous cell membrane camouflage, enabling active tumor targeting and cascade release in hypoxic environments: first releasing glucose oxidase (GOx) to consume glucose and exacerbate hypoxia, then triggering the burst release of chloroquine (CQ), thereby blocking lysosome-dependent nutrient recovery pathways. Experimental results show that this nanomedicine demonstrates a 9.75-fold increase in tumor accumulation, a 92.8% tumor inhibition rate, and an 80% survival improvement in PDAC orthotopic models, while exhibiting good biosafety.

This research not only reveals the mechanism by which PDAC compensates metabolically through lysosome-mediated autophagy and macropinocytosis under glucose deprivation but also provides a clinically translatable nanoplatform that can synergistically inhibit glucose metabolism and lysosomal function, offering a promising approach to enhance starvation therapy for PDAC and other metabolism-dependent tumors.

References:

DOI: 10.1002/adma.202519523

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