Bioengineered protein nanocarrier facilitating siRNA escape from lysosomes for targeted RNAi therapy in glioblastoma.

in Science advances by Yiliang 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

TLDR

  • Researchers develop a new nanocarrier called tHFn(+) that targets tumors and traverses the blood-brain barrier, enhancing siRNA delivery and suppressing gene expressions associated with GBM progression

Abstract

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.

Overview

  • Researchers designed and developed a new nanocarrier called tHFn(+) that uses human H-ferritin to target tumors and traverse the blood-brain barrier (BBB)
  • The tHFn(+) nanocarrier is capable of delivering small interfering RNA (siRNA) to glioblastoma (GBM) cells and suppressing gene expressions associated with GBM progression
  • The primary objective of the study is to develop a universal siRNA nanocarrier that can target various tumors and diseases, including GBM

Comparative Analysis & Findings

  • tHFn(+) nanocarriers significantly enhanced the uptake of different siRNAs and suppressed gene expressions associated with GBM progression
  • tHFn(+) nanocarriers exhibited exceptional therapeutic effects against glioma in vivo, advancing RNAi therapeutics beyond GBM for the treatment of various diseases
  • The study shows that tHFn(+) nanocarriers can traverse the BBB and target glioma in vivo by binding to its receptors, such as transferrin receptor 1

Implications and Future Directions

  • The findings of this study have significant implications for the development of RNAi therapeutics against various diseases, including GBM and other types of cancer
  • Future studies should investigate the safety and efficacy of tHFn(+) nanocarriers in humans and explore their potential applications in combination with other therapeutic strategies
  • The discovery of tHFn(+) nanocarriers may lead to the development of new therapeutic approaches for infectious diseases, neurological disorders, and other diseases that affect the brain
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