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

Abstract

AbstractFerrous 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.