Effective strategies that simultaneously target stromal barriers and tumor metabolism are urgently needed.<h4>Methods</h4>To overcome these challenges, we developed a dual-targeted, pH-responsive nanoplatform (PLA-THF-PEG/AV3/KH3 nanoparticles, termed AKNPs) that co-delivers AV3, a peptide antagonist of integrin α5 (ITGA5), and KH3, an allosteric inhibitor of phosphoglycerate mutase 1 (PGAM1). The gene discussed is PGAM1; the disease is neoplasm.