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

Ferrous iron (Fe2+) has more potent hydroxyl radical ((OH)-O-center dot)-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 Fe-0 nanoparticles (Fe-0-siRNA NPs) for self-reinforcing CDT via FHC downregulation. Upon internalization by cancer cells, pH-responsive Fe-0-siRNA NPs are degraded to release Fe2+ and FHC siRNA in acidic endo/lysosomes with the aid of oxygen (O-2). The accompanied O-2 depletion causes an intracellular pH decrease, which further promotes the degradation of Fe-0-siRNA NPs. In addition to initiating chemodynamic process, Fe2+-catalyzed (OH)-O-center dot generation facilitates endo/lysosomal escape of siRNA by disrupting the membranes, enabling FHC downregulation-enhanced CDT.

Automated summary

In this study, siRNA-embedded Fe-0 nanoparticles (Fe-0-siRNA NPs) were synthesized for self-reinforcing CDT via FHC downregulation. Upon internalization by cancer cells, pH-responsive Fe-0-siRNA NPs are degraded to release Fe2+ and FHC siRNA, promoting endo/lysosomal escape of siRNA and enhancing CDT through (OH)-O-center dot generation.