A novel ferritin-based siRNA delivery system demonstrates the potential for targeted glioblastoma therapy

A new research led by a professor. Fang Kelong and Yang Siyun of the Institute of Biophysics at the Chinese Academy of Sciences will introduce a new ferritin-based delivery system for small interfering RNAs (siRNAs) targeting glioblastoma (GBM).

Published in Science Advances, this study addresses key challenges in RNAI therapy, including poor cell intake, rapid clearance, and the difficulty of crossing the blood-brain barrier (BBB).

siRNAs have important potential for gene-specific therapies, particularly in inhibiting oncogenes, but their clinical applications are hampered by delivery disorders. To overcome these barriers, researchers have engineered ferritin, a native protein nanoparticle, to act as an effective carrier for siRNAs, and are specifically designed to pass through BBB and target GBM cells.

The researchers designed a series of ferritin variants with positively charged inner surfaces and truncated C-terminals. Through a systematic assessment of their structural properties and lysosomal escape capabilities, they obtained a new delivery carrier – THFN(+).

This nanocarrier releases siRNA in the weakly acidic environment of the endosome, degrading while exposing the internal positive charge to promote lysosome escape.

Cryo-Electron microscopy analysis confirmed the mechanism underlying its pH responsiveness. Truncation of the C-terminus weakens interfacial interactions and allows for degradation in an acidic endosome environment.

In vitro experiments, THFN(+) was shown to efficiently deliver siRNA to the cytoplasm, leading to effective gene knockdown. Both in vitro and in vivo studies confirmed that THFN(+) can successfully pass through the BBB and target GBM in particular.

Furthermore, Sitert and Siegfr, delivered from THFN(+), showed significant therapeutic effects in the mouse model.

The ferritin-based carrier developed in this study showed high efficiency and wide applicability in the delivery of siRNA molecules targeting a variety of genes, providing new strategies and platforms for RNAi therapy in cancer, genetic disorders, and other related diseases, with promising clinical applications.