Cu-doped dendritic biodegradable nanoplatforms for augmenting cuproptosis and tumor-starvation therapy through mitochondrial metabolic cascade modulation

Reprogramming of branched-chain amino acid (BCAA) metabolism is a key mechanism promoting pancreatic cancer progression. While gabapentin (Gp) can inhibit BCAA catabolism by targeting branched-chain amino acid aminotransferase 1 (BCAT1), its efficacy is limited by inefficient delivery and compensatory mitochondrial metabolism. To address this, we developed a novel copper ionophore-functionalized mesoporous silica nanoplatform (XQ/Gp@CMSNs) for synergistic cuproptosis and tumor-starvation therapy. The designed nanoparticles exhibit excellent pancreatic cancer-targeting capability via XQ-2d aptamer modification and acid-responsive drug release within the tumor microenvironment. Upon internalization, XQ/Gp@CMSNs simultaneously induce mitochondrial copper overload and disrupt BCAA metabolism, leading to dihydrolipoamide S-acetyltransferase (DLAT) oligomerization, ferredoxin 1 (FDX1) downregulation, and tricarboxylic acid (TCA) cycle suppression. Both <i>in vitro</i> and <i>in vivo</i> studies demonstrated potent antitumor efficacy with minimal systemic toxicity. Metabolomic analyses further confirmed synergistic BCAA metabolic inhibition and copper-induced mitochondrial dysfunction. This work presents a promising metabolic intervention strategy for pancreatic cancer through targeted nanomedicine.