Acta pharmaceutica Sinica. BMar 5, 2025

Iron and gene-silencing RNA packed in protein cages work together to trigger cancer cell death for therapy

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 16, 2026

Abstract

HFn@Fe/siGPX4 significantly inhibits tumor growth through enhanced ferroptosis.

Ferroptosis is a type of cell death that is influenced by iron levels within cancer cells.
The antioxidant enzyme glutathione peroxidase 4 (GPX4) limits the effectiveness of ferroptosis in cancer therapy.
HFn@Fe/siGPX4 combines iron and siRNA targeting GPX4 to disrupt antioxidant defenses and promote ferroptosis.
The method used for loading siGPX4 into ferritin nanocages improves gene delivery efficiency compared to previous techniques.
Excess iron from the delivery system can induce ferroptosis by generating reactive oxygen species (ROS).
HFn@Fe/siGPX4 facilitates effective gene silencing by allowing siGPX4 to escape from lysosomes in cancer cells.

Simplified

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 theandresults 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. in vitro in vivo

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Competing interests

The authors have no conflicts of interest to declare.

PubMed

Iron and gene-silencing RNA packed in protein cages work together to trigger cancer cell death for therapy

Abstract

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Abstract

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Related papers

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