Self‐Amplified Nanomedicine Enables Lysosomal Blockade to Potentiate Starvation Therapy of Pancreatic Ductal Adenocarcinoma

ABSTRACT Starvation therapy targeting the metabolic vulnerability of pancreatic ductal adenocarcinoma (PDAC) holds great potential; however, analyses of clinical samples and orthotopic models reveal that its efficacy is undermined by lysosome‐mediated metabolic compensation. To disrupt this metabolic adaptability, we herein engineer a homotypic membrane‐camouflaged nanomedicine capable of hypoxia‐responsive cascade drug release and enhanced tumor accumulation. The resulting nanomedicine performs a hypoxia‐induced phase transition that first liberates glucose oxidase to intensify oxygen deprivation and subsequently triggers burst release of chloroquine. Such a design of self‐amplified relay drug release ensures effective starvation induction and precise lysosomal alkalization, thereby shutting down lysosome‐mediated nutrient recycling. In a xenograft orthotopic PDAC model, this nanomedicine achieves 9.75‐fold increase in tumor accumulation, robust tumor inhibition of 92.8%, and an elevated survival rate of 80% with favorable biosafety. Collectively, our findings highlight lysosomal disruption as a therapeutic lever to potentiate starvation therapy and provide a clinically actionable nanoplatform to enhance metabolic interventions for other metabolically vulnerable malignancies.