The brief lifetime of reduced O2 levels and oxygen species during ferroptosis in cancer cell lines undermines the ferroptosis efficacy. Enhancing the effectiveness of real-time created active oxygen species is crucial for pancreatic adenocarcinoma. The Evofosfamide (EFA) encapsulated polydopamine (PD)-iron (Fe) nanoparticles (Fe/PD-EFA) were modified with unsaturated liposomes (Lipo) to address the limitations of conventional ferroptosis therapy. The Lipo@Fe/PD-EFA can interact with H2O2 to generate center dot OH, which subsequently targets Lipo, resulting in the formation of a phospholipid peroxide radical (LOO center dot) and a radical intermediate (L center dot) to mitigate the detrimental effects of the center dot OH. Liposomes facilitate oxygen consumption and augment lipid peroxidation, thereby exacerbating hypoxia at the site of pancreatic cancer. The EFA can be activated by reductase in cancer cell lines under a hypoxic milieu, which diminishes free radicals through the reductase enzyme and disrupts the adjacent biomacromolecules' structure, thereby facilitating the synergistic therapy of chemotherapy and ferroptosis in Panc-1 cells. This study integrates improved ferroptosis with hypoxia-activated chemotherapy to generate an effective and targeted tumoricidal impact, perhaps offering a promising treatment for pancreatic adenocarcinoma (PDAC) in the future.