siRNA can inhibit the expression of specific oncogenes, showing promising anti-tumor potential. However, its clinical application faces several obstacles, such as the hydrophilic nature and negative charge hindering cellular uptake, insufficient lysosomal escape leading to degradation risks, poor tumor targeting, and rapid renal clearance. Especially in the treatment of glioblastoma, traditional drug delivery systems face the immense challenge of the blood-brain barrier. Therefore, developing siRNA delivery carriers that can cross the blood-brain barrier and specifically target tumors has become a key breakthrough in advancing RNAi therapy for brain tumors.

        On February 19, 2025, a research paper titled "Bioengineered protein nanocarrier facilitating siRNA escape from lysosomes for targeted RNAi therapy in glioblastoma" was published in Science Advances by the team of Fan Kelong and Yan Xiyun from the Institute of Biophysics, Chinese Academy of Sciences. The team designed an siRNA delivery system targeting glioblastoma using ferritin. Over more than a decade of systematic research, the team revealed that human heavy-chain ferritin (HFn) has the unique ability to specifically recognize tumors and cross the blood-brain barrier. However, delivering siRNA with ferritin still faces the critical challenge of overcoming lysosomal escape. Building upon this work, the researchers modified ferritin to meet the specific requirements of siRNA delivery and successfully constructed a ferritin-based carrier with lysosomal escape functionality.

        The researchers designed a series of ferritin mutants with positively charged inner surfaces and truncated C-termini. Through systematic evaluation of their structural properties and lysosomal escape abilities, they identified a novel delivery carrier—tHFn(+). This nanocarrier can dissociate in the acidic environment of the endosome to release siRNA while exposing its internal positive charge, mediating lysosomal escape. Cryo-electron microscopy structural analysis confirmed the weak acid-responsive mechanism of this protein, where truncating the C-terminus weakens the interface interactions, allowing it to dissociate in the acidic environment of the endosome. In vitro experiments demonstrated that this carrier can effectively deliver siRNA to the cytoplasm, ultimately leading to efficient gene silencing. Both in vitro and in vivo studies showed that tHFn(+) can cross the blood-brain barrier and specifically target glioblastoma. Moreover, siTERT and siEGFR delivered by the tHFn(+) carrier exhibited excellent therapeutic effects in mouse models.

        The ferritin carrier designed in this study demonstrates high efficiency and versatility in delivering siRNA targeting different molecular sites, providing a new strategy and platform for RNAi therapy in cancers, genetic diseases, and other related conditions, with broad clinical application prospects.