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