Iron-siRNA Nanohybrids for Enhanced Chemodynamic Therapy via Ferritin Heavy Chain Downregulation

Ferrous iron (Fe²⁺ ) has more potent hydroxyl radical (⋅OH)-generating ability than other Fenton-type metal ions, making Fe-based nanomaterials attractive for chemodynamic therapy (CDT). However, because Fe²⁺ can be converted by ferritin heavy chain (FHC) to nontoxic ferric form and then sequestered in ferritin, therapeutic outcomes of Fe-mediated CDT agents are still far from satisfactory. Here we report the synthesis of siRNA-embedded Fe⁰ nanoparticles (Fe⁰ -siRNA NPs) for self-reinforcing CDT via FHC downregulation. Upon internalization by cancer cells, pH-responsive Fe⁰ -siRNA NPs are degraded to release Fe²⁺ and FHC siRNA in acidic endo/lysosomes with the aid of oxygen (O₂ ). The accompanied O₂ depletion causes an intracellular pH decrease, which further promotes the degradation of Fe⁰ -siRNA NPs. In addition to initiating chemodynamic process, Fe²⁺ -catalyzed ⋅OH generation facilitates endo/lysosomal escape of siRNA by disrupting the membranes, enabling FHC downregulation-enhanced CDT.