Iron and siRNA co-encapsulated ferritin nanocages induce ferroptosis synergistically for cancer therapy  

作　　者：Danni Liu Yaoqi Wang Qi Sun Dong Mei Xiaoling Wang Yan Su Jie Zhang Ran Huo Yang Tian Siyu Liu Shuang Zhang Chunying Cui 

机构地区：[1]School of Pharmaceutical Sciences,Capital Medical University,Beijing 100069,China [2]Beijing Area Major Laboratory of Peptide and Small Molecular Drugs,Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China,Beijing Laboratory of Biomedical Materials,Beijing 100069,China [3]Laboratory for Clinical Medicine,Capital Medical University,Beijing 100069,China [4]Department of Pharmacy,Beijing Children’s Hospital,Capital Medical University,National Center for Children’s Health,Beijing 100045,China [5]Medical Oncology Department,Pediatric Oncology Center,Beijing Children’s Hospital,Capital Medical University,National Center for Children’s Health,Beijing 100045,China

出　　处：《Acta Pharmaceutica Sinica B》2025年第1期526-541,共16页药学学报(英文版)

基　　金：supported by the National Natural Science Foundation of China(81502688);Cooperation Research Funding of Capital Medical University(2020KJ000514,China);Cooperation Research Funding of Capital Medical University(2023KJ000814,China);R&D Program of Beijing Municipal Education Commission(KM202210025024,China).

摘　　要：Ferroptosis has received great attention as an iron-dependent programmed cell death for efficient cancer therapy.However,with the accumulation of iron in tumor cells,the antioxidant system is activated by reducing glutathione(GSH)with glutathione peroxidase 4(GPX4),which critically limits the ferroptosis therapeutic effect.Herein,an iron and GPX4 silencing siRNA(siGPX4)co-encapsulated ferritin nanocage(HFn@Fe/siGPX4)was developed to enhance ferroptosis by disruption of redox homeostasis and inhibition of antioxidant enzyme synergistically.The siGPX4 were loaded into the nanocages by pre-incubated with iron,which could significantly improve the loading efficiency of the gene drugs when compared with the reported gene drug loading strategy by ferritin nanocages.And more iron was overloaded into the ferritin through the diffusion method.When HFn@Fe/siGPX4 was taken up by human breast cancer cell MCF-7 in a TfR1-mediated pathway,the excess iron ions in the drug delivery system could for one thing induce ferroptosis by the production of reactive oxygen species(ROS),for another promote siGPX4 escaping from the lysosome to exert gene silencing effect more effectively.Both the in vitro and in vivo results demonstrated that HFn@Fe/siGPX4 could significantly inhibit tumor growth by synergistical ferroptosis.Thus,the developed HFn@Fe/siGPX4 afforded a combined ferroptosis strategy for ferroptosis-based antitumor as well as a novel and efficient gene drug delivery system.

关 键 词：Ferroptosis FERRITIN Iron homeostasis SIRNA Gene silencing Glutathione peroxidase 4 ANTITUMOR Lipid peroxidation 

分 类 号：R73[医药卫生—肿瘤]