RNA four-way junction (4WJ) for spontaneous cancer-targeting, effective tumor-regression, metastasis suppression, fast renal excretion and undetectable toxicity

Xin Li, Kai Jin, Tzu Chun Cheng, You Cheng Liao, Wen Jui Lee, Abhjeet S. Bhullar, Li Ching Chen, Piotr Rychahou, Mitch A. Phelps, Yuan Soon Ho, Peixuan Guo

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

The field of RNA therapeutics has been emerging as the third milestone in pharmaceutical drug development. RNA nanoparticles have displayed motile and deformable properties to allow for high tumor accumulation with undetectable healthy organ accumulation. Therefore, RNA nanoparticles have the potential to serve as potent drug delivery vehicles with strong anti-cancer responses. Herein, we report the physicochemical basis for the rational design of a branched RNA four-way junction (4WJ) nanoparticle that results in advantageous high-thermostability and -drug payload for cancer therapy, including metastatic tumors in the lung. The 4WJ nanostructure displayed versatility through functionalization with an anti-cancer chemical drug, SN38, for the treatment of two different cancer models including colorectal cancer xenograft and orthotopic lung metastases of colon cancer. The resulting 4WJ RNA drug complex spontaneously targeted cancers effectively for cancer inhibition with and without ligands. The 4WJ displayed fast renal excretion, rapid body clearance, and little organ accumulation with undetectable toxicity and immunogenicity. The safety parameters were documented by organ histology, blood biochemistry, and pathological analysis. The highly efficient cancer inhibition, undetectable drug toxicity, and favorable Chemical, Manufacturing, and Control (CMC) production of RNA nanoparticles document a candidate with high potential for translation in cancer therapy.

Original languageEnglish
Article number122432
JournalBiomaterials
Volume305
DOIs
StatePublished - Mar 2024

Bibliographical note

Publisher Copyright:
© 2023

Keywords

  • Chemotherapeutics
  • Drug delivery
  • RNA nanoparticle
  • RNA nanotechnology
  • SN38

ASJC Scopus subject areas

  • Biophysics
  • Bioengineering
  • Ceramics and Composites
  • Biomaterials
  • Mechanics of Materials

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