MOE Key Laboratory for Analytical Science of Food Safety and Biology, Engineering Technology Research Center on Reagent and Instrument for Rapid Detection of Product Quality and Food Safety in Fujian Province, College of Chemistry, Fuzhou University, 350108, Fuzhou, China.
Departments of Diagnostic Radiology, Surgery, Chemical and Biomolecular Engineering and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, 117597, Singapore, Singapore.
Angew Chem Int Ed Engl. 2023 May 22;62(22):e202302255. doi: 10.1002/anie.202302255. Epub 2023 Apr 21.
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.
二价铁 (Fe ) 比其他芬顿型金属离子具有更强的羟基自由基 (⋅OH) 生成能力，这使得基于 Fe 的纳米材料在化学动力学治疗 (CDT) 中具有吸引力。然而，由于铁可以被铁蛋白重链 (FHC) 转化为无毒的三价铁形式，然后被铁蛋白隔离，因此 Fe 介导的 CDT 试剂的治疗效果仍然远未令人满意。在这里，我们报告了通过下调 FHC 来合成嵌入 siRNA 的 Fe 纳米颗粒 (Fe -siRNA NPs) ，以进行自我强化的 CDT。在被癌细胞内化后，在氧气 (O ) 的帮助下，pH 响应性的 Fe -siRNA NPs 在酸性内体/溶酶体中降解，释放 Fe 和 FHC siRNA。伴随的 O 消耗导致细胞内 pH 下降，这进一步促进了 Fe -siRNA NPs 的降解。除了引发化学动力学过程外，Fe 催化的 ⋅OH 生成还通过破坏膜来促进 siRNA 的内体/溶酶体逃逸，从而实现 FHC 下调增强的 CDT。
