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Synthesis of ionizable lipopolymers using split-Ugi reaction for pulmonary delivery of various size RNAs and gene editing

Author

Listed:
  • K. Yu. Vlasova

    (College of Pharmacy at Oregon State University)

  • A. Kerr

    (University of Helsinki)

  • N. D. Pennock

    (Oregon Health & Science University)

  • A. Jozic

    (College of Pharmacy at Oregon State University)

  • D. K. Sahel

    (College of Pharmacy at Oregon State University)

  • M. Gautam

    (College of Pharmacy at Oregon State University)

  • N. T. V. Murthy

    (College of Pharmacy at Oregon State University)

  • A. Roberts

    (Oregon Health & Science University)

  • M. W. Ali

    (University of Helsinki)

  • K. D. MacDonald

    (College of Pharmacy at Oregon State University
    Oregon Health & Science University)

  • J. M. Walker

    (Oregon Health & Science University
    Oregon Health & Science University
    Oregon Health & Science University)

  • R. Luxenhofer

    (University of Helsinki)

  • G. Sahay

    (College of Pharmacy at Oregon State University
    Oregon State University & Oregon Health & Sciences University)

Abstract

We present an efficient method for synthesizing cationic poly(ethylene imine) derivatives using the multicomponent split-Ugi reaction to create a library of functional ionizable lipopolymers. Here we show 155 polymers, formulated into polyplexes, to establish structure-activity relationships essential for endosomal escape and transfection. A lead structure is identified, and lipopolymer-lipid hybrid nanoparticles are developed to deliver mRNA to lung endothelium and immune cells, including T cells, with low in vivo toxicity. These nanoparticles show significant improvements in mRNA delivery to the lung compared to in vivo-JetPEI® and demonstrate effective delivery of therapeutic mRNA(s) of various sizes. IL-12 mRNA-loaded nanoparticles delay Lewis Lung cancer progression, while human CFTR mRNA restores CFTR protein function in CFTR knockout mice. Additionally, we demonstrate in vivo CRISPR-Cas9 mRNA delivery, achieving gene editing in lung tissue and successful PD-1 knockout in T cells in mice. These results highlight the platform’s potential for systemic gene therapy delivery.

Suggested Citation

  • K. Yu. Vlasova & A. Kerr & N. D. Pennock & A. Jozic & D. K. Sahel & M. Gautam & N. T. V. Murthy & A. Roberts & M. W. Ali & K. D. MacDonald & J. M. Walker & R. Luxenhofer & G. Sahay, 2025. "Synthesis of ionizable lipopolymers using split-Ugi reaction for pulmonary delivery of various size RNAs and gene editing," Nature Communications, Nature, vol. 16(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59136-z
    DOI: 10.1038/s41467-025-59136-z
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    References listed on IDEAS

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    1. Lucy Allen & Lorna Allen & Siobhan B. Carr & Gwyneth Davies & Damian Downey & Marie Egan & Julian T. Forton & Robert Gray & Charles Haworth & Alexander Horsley & Alan R. Smyth & Kevin W. Southern & Ja, 2023. "Future therapies for cystic fibrosis," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. He Zhang & Liang Zhang & Ang Lin & Congcong Xu & Ziyu Li & Kaibo Liu & Boxiang Liu & Xiaopin Ma & Fanfan Zhao & Huiling Jiang & Chunxiu Chen & Haifa Shen & Hangwen Li & David H. Mathews & Yujian Zhang, 2023. "Algorithm for optimized mRNA design improves stability and immunogenicity," Nature, Nature, vol. 621(7978), pages 396-403, September.
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