A new study led by Profs. FAN Kelong and YAN Xiyun from the Institute of Biophysics of the Chinese Academy of Sciences introduces a novel ferritin-based delivery system for small interfering RNA (siRNA) targeting glioblastoma (GBM), a breakthrough that could enhance RNA interference (RNAi) therapies for cancer treatment. 

The study, published in Science Advances on February 19, addresses key challenges in RNAi therapy, including poor cellular uptake, rapid clearance, and the difficulty of crossing the blood-brain barrier (BBB).

siRNA holds significant potential for gene-specific therapies, particularly in inhibiting oncogenes, but its clinical application has been hampered by delivery obstacles. To overcome these barriers, the researchers engineered ferritin, a natural protein nanoparticle, to serve as an effective carrier for siRNA, specifically designed to cross the BBB and target GBM cells.

The researchers designed a series of ferritin variants with positively charged inner surfaces and truncated C-terminal. Through systematic evaluation of their structural properties and lysosomal escape capability, they obtained a novel delivery carrier-tHFn(+).

This nanocarrier disassembles in the weakly acidic environment of endosomes to release siRNA while exposing internal positive charges to facilitate lysosomal escape.

Cryo-electron microscopy analysis confirmed the mechanism underlying its pH responsiveness: truncation of the C-terminus weakens interfacial interactions, allowing disassembly in the acidic endosomal environment.

In vitro experiments showed that tHFn(+) efficiently delivered siRNA into the cytoplasm, resulting in effective gene knockdown. Both in vitro and in vivo studies confirmed that tHFn(+) could successfully cross the BBB and specifically target GBM.

Additionally, siTERT and siEGFR delivered by tHFn(+) exhibited remarkable therapeutic effects in mouse models.

The ferritin-based carrier developed in this study demonstrated high efficiency and broad applicability in delivering siRNA molecules targeting various genes, providing a novel strategy and platform for RNAi therapy in cancer, genetic disorders, and other related diseases, with promising clinical applications.

Schematic Diagram of the Design, Screening, and Application of Ferritin-based siRNA Carrier for Targeted Glioblastoma Therapy (Image by FAN Kelong's group)