Gemcitabine is the first-line chemotherapeutic agent and the gold standard for pancreatic cancer. However, the short blood half-life and drug resistance limit its therapeutic efficacy in clinic. Recent advancements in nanotechnology offered a potent approach for improving gemcitabine delivery and efficacy. In this study, we present the design and synthesis of gemcitabine-loaded nanoparticles utilizing gemcitabine monophosphate (GMP) and metal ions via a coordination-precipitation strategy. Firstly, a series of metal ions, including Ca²⁺, Fe³⁺, Mn²⁺, Gd³⁺ and Lu³⁺, were mixed with GMP to form nanoparticles (Metal-GMP NPs) employing a reverse-phase microemulsion method. The morphology of the as-prepared Metal-GMP NPs were characterized by transmission electron microscopy while the hydrated particle size, polydispersion index and zeta potential were measured by dynamic light scattering. Additionally, the encapsulation efficiency and loading ratio of GMP, as well as the molar ratio of GMP to metals were quantified through high performance liquid chromatography (HPLC) and inductively coupled plasma mass spectrometry (ICP-MS). Subsequently, the anti-tumor efficacy of the as-prepared Metal-GMP NPs were studied by CCK8 assay on three different pancreatic cancer cell lines. The screening results suggested that Fe-GMP NPs has the preferable anti-tumor activity as well as the obvious synergistic effect between metal ions and drugs. The further mechanism studies revealed that Fe-GMP NPs could generate enough cytotoxic reactive oxygen species (ROS) through Fenton-like reactions within tumor cells. And simultaneously, the intracellular reduced glutathione (GSH) was consumed, thereby disrupting the redox homeostasis and enhancing GEM efficacy. Finally, the therapeutic efficacy and bio-safety of Fe-GMP NPs were investigated on the subcutaneous tumor-bearing model. The in vivo results demonstrated that Fe-GMP NPs exhibited better therapeutic efficacy rather than GMP free drugs alone. Meanwhile, the bio-safety assessment confirmed the absence of significant toxicity or side effects associated with Fe-GMP NP treatment. This work combines metal ions with gemcitabine in the manner of chemistry, providing a highly promising strategy for the delivery and sensitization of gemcitabine in pancreatic cancer therapy.