An Engineered Iron-Based MOF for siRNA Delivery Targeting Chemotherapy-Resistant Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) remains one of the most aggressive and treatment-resistant malignancies. Herein, we report a glutathione-responsive nanoplatform based on nanoparticles of the mesoporous iron MOF MIL-100(Fe) functionalized with linear polyethyleneimine (LPEI), designed for synergistic chemo/gene/ferroptosis therapy. LPEI imparts enhanced colloidal and chemical stability in physiological media, facilitates lysosomal escape, and enables efficient immobilization and protection of siRNA targeting vimentin (siVIM), a marker of drug resistance and metastasis. Simultaneously, gemcitabine (GEM), a chemotherapeutic agent, is encapsulated within the mesopores of MIL-100. The cationic PEI coating not only improves tumor penetration and phagocytosis evasion but also protects siRNA from nuclease degradation. Upon GSH-triggered MOF degradation in the tumor microenvironment, coordinated release of Fe ions, GEM, and siVIM leads to ferroptosis, S-phase arrest, and vimentin silencing, respectively. This results in 59.6% apoptotic cell death and 74.9% S-phase arrest in TNBC cells. In vivo, the MIL-100@GEM-LPEI@siVIM formulation achieves 84% tumor growth inhibition in a 4T1 murine model, with no observable toxicity. This study presents a multifunctional Fe-MOF-based delivery platform that combines gene silencing, chemotherapy, and ferroptosis to effectively treat triple-negative breast cancer (TNBC), offering a promising preclinical approach to overcoming therapeutic resistance.