Ferritin-Based siRNA System for Glioblastoma Therapy

A groundbreaking study led by Professors Fan Kelong and Yan Xiyun from the Institute of Biophysics of the Chinese Academy of Sciences has developed a novel ferritin-based delivery system for small interfering RNA (**siRNA**) aimed at treating glioblastoma (GBM). This advancement could significantly improve the efficacy of RNA interference (RNAi) therapies utilized in cancer treatment.

Challenges in Current RNAi Therapies

While siRNA has shown considerable potential in gene-specific therapies, particularly for inhibiting oncogenes, its clinical application has been hindered by several challenges:

• Poor cellular uptake: siRNA molecules often struggle to penetrate cell membranes efficiently.
• Rapid clearance: Once introduced into the body, siRNA is frequently quickly eliminated.
• Blood-brain barrier (BBB) penetration: The protective barrier limits therapeutic access to brain tumors such as GBM.

The Innovative Ferritin-Based System

To overcome these significant barriers, the researchers engineered ferritin—a natural protein nanoparticle—to create a highly effective siRNA carrier. The engineered variant, termed tHFn(+), features positively charged inner surfaces and a truncated C-terminal, enabling it to effectively cross the BBB and selectively target GBM cells.

Mechanism of Action

The ferritin-based platform was designed to respond to the acidic environment of endosomes:

• The tHFn(+) disassembles in weakly acidic conditions to release its siRNA payload.
• This mechanism involves the exposure of internal positive charges that facilitate lysosomal escape, crucial for successful gene delivery.

Through cryo-electron microscopy analysis, the team established that the truncation of the C-terminus weakens interfacial interactions, thus promoting disassembly within the acidic endosomal compartment.

Experimental Validation

The efficacy of the tHFn(+) carrier was verified through a series of in vitro and in vivo experiments:

Therapeutic Implications

The therapeutic potential of the tHFn(+) carrier was further highlighted by targeting specific genes implicated in GBM.

Notably, siRNA targeting TERT and EGFR, when delivered via tHFn(+), demonstrated remarkable therapeutic effects in mouse models, showcasing this strategy's broad applicability for delivering siRNA targeting various oncogenes.

Future Applications

This ferritin-based siRNA delivery system opens the door for enhanced RNAi therapies not just for GBM, but potentially for other cancer types and genetic disorders. Its proven ability to:

• Improve siRNA delivery efficiency
• Facilitate BBB penetration
• Enhance therapeutic efficacy

positions it as a promising platform for further clinical applications.

Conclusion

The research conducted by the Institute of Biophysics represents a significant step forward in the fight against glioblastoma. By addressing key delivery issues, this novel ferritin-based system exemplifies innovation in cancer therapy and highlights the potential of engineered biopharmaceuticals to navigate complex biological barriers.

Further Reading

For more detailed information, refer to the original study published in Science Advances by Yiliang Jin et al., titled Bioengineered protein nanocarrier facilitating siRNA escape from lysosomes for targeted RNAi therapy in glioblastoma (2025).

References

• [1] Jin, Y., et al. (2025). Bioengineered protein nanocarrier facilitating siRNA escape from lysosomes for targeted RNAi therapy in glioblastoma. Science Advances.
• [2] Science X. (2025). Novel ferritin-based siRNA delivery system shows promise for targeted glioblastoma therapy. Retrievable from Phys.org.

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