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. 2023 May 22;62(22):e202302255.
doi: 10.1002/anie.202302255. Epub 2023 Apr 21.

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

Jun Wang  1 , Hongye Ding  1 , Yang Zhu  1   2 , Yina Liu  1 , Meili Yu  1 , Huilan Cai  1 , Rujiang Ao  1 , Hongwei Huang  1 , Peng Gong  1 , Yaxin Liao  1 , Zhaolin Chen  1 , Lisen Lin  1 , Xiaoyuan Chen  2   3 , Huanghao Yang  1
Affiliations

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

Jun Wang et al. Angew Chem Int Ed Engl. .

Abstract

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.

Keywords: Chemodynamic Therapy; Fenton Reaction; Ferritin Heavy Chain; Iron Nanoparticles; Small Interfering RNA.

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