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TitleBioengineered protein nanocarrier facilitating siRNA escape from lysosomes for targeted RNAi therapy in glioblastoma.
Journal, issue, pagesSci Adv, Vol. 11, Issue 8, Page eadr9266, Year 2025
Publish dateFeb 21, 2025
AuthorsYiliang Jin / Baoli Zhang / Jianru Li / Zhenxi Guo / Chen Zhang / Xuehui Chen / Long Ma / Zhuoran Wang / Haiyin Yang / Yong Li / Yuhua Weng / Yuanyu Huang / Xiyun Yan / Kelong Fan /
PubMed AbstractRNA interference (RNAi) represents a promising gene-specific therapy against tumors. However, its clinical translation is impeded by poor performance of lysosomal escape and tumor targeting. This ...RNA interference (RNAi) represents a promising gene-specific therapy against tumors. However, its clinical translation is impeded by poor performance of lysosomal escape and tumor targeting. This challenge is especially prominent in glioblastoma (GBM) therapy, necessitating the penetration of the blood-brain barrier (BBB). Leveraging the intrinsic tumor-targeting and BBB traversing capability of human H-ferritin, we designed a series of ferritin variants with positively charged cavity and truncated carboxyl terminus, termed tHFn(+). These nanocarriers respond to weak acid and disassemble in endosomal compartments, exposing the internal positive charges to facilitate the lysosomal escape of loaded small interfering RNA (siRNA). Functioning as universal siRNA nanocarriers, tHFn(+) significantly enhanced the uptake of different siRNAs and suppressed gene expressions associated with GBM progression. Furthermore, tHFn(+) traversed the BBB and targeted glioma in vivo by binding to its receptors (e.g., transferrin receptor 1). tHFn(+)-delivered siRNAs exhibited exceptional therapeutic effects against glioma in vivo, advancing RNAi therapeutics beyond GBM for the treatment of various diseases.
External linksSci Adv / PubMed:39970222 / PubMed Central
MethodsEM (single particle)
Resolution1.73 Å
Structure data

62216

9kay

EMDB-62216, PDB-9kay:
Bioengineered protein nanocarrier facilitating siRNA escape from lysosomes for targeted RNAi therapy in glioblastoma
Method: EM (single particle) / Resolution: 1.73 Å

Source
  • Homo sapiens (Human) (human)
  • homo sapiens (human)
KeywordsMETAL TRANSPORT / Bioengineered ferritin / Lysosomal escape / siRNA delivery / Glioblastoma targeted therapy / EGFR and TERT

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