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Discrete Immolative Guanidinium Transporters deliver mRNA to specific organs and red blood cells

Author

Listed:
  • Zhijian Li

    (Stanford University)

  • Aloysius Ee

    (Stanford University
    Stanford University
    70 Nanyang Drive)

  • Laura Amaya

    (Stanford University
    Stanford University School of Medicine)

  • Jennifer L. Hamad

    (Stanford University
    Stanford University)

  • Pavan K. Yadav

    (Stanford University)

  • Sean K. Wang

    (Stanford University
    Stanford University School of Medicine)

  • Howard Y. Chang

    (Stanford University
    Stanford University
    Amgen Research)

  • Paul A. Wender

    (Stanford University
    Stanford University)

Abstract

RNA medicine is an emerging groundbreaking technology for the prevention and treatment of disease. However, tools to deliver messenger RNA (mRNA) and other polyanions (circRNA, saRNA, pDNA, CRISPR-Cas, reprogramming factors) are required to advance current RNA therapies and address next generation challenges. Existing delivery systems often suffer from laborious syntheses, limited organ selectivity, formulation complexity, and undesired inflammatory responses. Here, we report novel mRNA delivery systems termed Discrete Immolative Guanidinium Transporters (DIGITs), which are synthesized convergently in as few as 4 steps. Unlike most cationic (ammonium) delivery systems, DIGITs are based on cationic guanidinium moieties, which complex mRNA at acidic pH and undergo irreversible neutralization at physiological pH to enable efficient RNA release. Systematic evaluation of structural variations and formulations have led to DIGIT/mRNA complexes that selectively target lung, spleen, and immature red blood cells in peripheral blood in female mice model. DIGIT/mRNA delivery systems show minimal toxicity based on cell viability and biochemical assays, supporting their future utility in biomedical applications.

Suggested Citation

  • Zhijian Li & Aloysius Ee & Laura Amaya & Jennifer L. Hamad & Pavan K. Yadav & Sean K. Wang & Howard Y. Chang & Paul A. Wender, 2025. "Discrete Immolative Guanidinium Transporters deliver mRNA to specific organs and red blood cells," Nature Communications, Nature, vol. 16(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-62200-3
    DOI: 10.1038/s41467-025-62200-3
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