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

作者：Jun Wang, Hongye Ding, Yang Zhu, Yina Liu, Meili Yu, Huilan Cai, Rujiang Ao, Hongwei Huang, Peng Gong, Yaxin Liao, Zhaolin Chen, Lisen Lin, Xiaoyuan Chen, Huanghao Yang · 发表于：Angewandte Chemie International Edition · 年份：2023 · DOI：10.1002/anie.202302255 · 被引用次数：59 · 研究领域：Advanced biosensing and bioanalysis techniques、RNA Interference and Gene Delivery、Nanoplatforms for cancer theranostics

Abstract Ferrous iron (Fe 2+ ) 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 2+ 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 Fe 2+ 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, Fe 2+ ‐catalyzed ⋅OH generation facilitates endo/lysosomal escape of siRNA by disrupting the membranes, enabling FHC downregulation‐enhanced CDT.