Engineering of polydopamine/hyaluronic acid-coated iron-doped MOF with gemcitabine: successful chemo and chemodynamic therapy in pancreatic cancer cells

Chemodynamic therapy (CDT) is an innovative oncological therapeutic approach that utilizes CDT agents to change hydrogen peroxide (H 2 O 2 ) into hydroxyl radicals (·OH), the toxic reactive oxygen species (ROS), through Fenton/Fenton-like processes, thereby triggering cell death. This therapy technique has been extensively studied due to its slight invasiveness and good tumor specificity, rendering it a prominent subject of investigation. In this study, to improve anticancer potential by GSH depletion and tumor-targeted-amplified chemo/chemodynamic therapy (CDT/CT), polydopamine (PD)/hyaluronic acid (HA)-coated Fe 2+ -doped zeolite imidazole frameworks-8 (FZ MOF) was developed and used to encapsulate the chemotherapy drug gemcitabine (GEM), via charge, hydrophobic interactions, and π-π stacking. In a GSH and acidic milieu, the obtained PD/HA-covered GEM-carrying FZ MOFs (PHGFZ MOFs) enhanced the release of GEM and Fe 2+ and demonstrated acidity-activated •OH generation. In addition to significantly increasing •OH accumulations by GSH consuming via PD in conjunction with the Fe 2+ /Fe 3+ to cause lipid peroxidation and mitochondrial damage, the PHGFZ MOFs internalized by BxPC-3 cells through effective CD44-facilitated endocytosis also achieved intracellular GEM release, which in turn triggered apoptosis and ferroptosis. Crucially, the PHGFZ MOFs demonstrated promising tumor-targeted treatment by effectively inhibiting pancreatic cancer cells and exhibiting excellent biosafety.