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Ionizable polymeric micelles (IPMs) for efficient siRNA delivery

Author

Listed:
  • Ziyu Zhou

    (East China Normal University
    East China Normal University)

  • Yu Feng

    (East China Normal University)

  • Mingzhou Jiang

    (Huashan Hospital of Fudan University)

  • Zijun Yao

    (East China Normal University)

  • Jing Wang

    (East China Normal University)

  • Feng Pan

    (Shanghai Fudan University)

  • Rulan Feng

    (East China Normal University)

  • Chong Zhao

    (East China Normal University)

  • Yinyu Ma

    (Fudan University)

  • Jinge Zhou

    (Kunming Medical University)

  • Lei Sun

    (East China Normal University
    University of California San Diego)

  • Xiaotian Sun

    (Huashan Hospital of Fudan University)

  • Changyou Zhan

    (Shanghai Fudan University
    Fudan University)

  • Xiao He

    (East China Normal University
    East China Normal University)

  • Kuan Jiang

    (Fudan University
    Fudan University)

  • Jiahui Yu

    (East China Normal University)

  • Zhiqiang Yan

    (East China Normal University
    East China Normal University)

Abstract

Lipid nanoparticles (LNPs) are widely used for nucleic acid delivery but face challenges like limited targeting and accelerated blood clearance (ABC) effect. We design three ionizable oligomers (IOs) that, with polylactide-polyethylene glycol (PLA-PEG), form a potential siRNA delivery system, named Ionizable Polymeric Micelles (IPMs). The siRNA encapsulated IPMs escape from lysosomes upon cellular uptake, and silence the target gene. A fibroblast activation protein inhibitor modified IPMs (FAPi-IPMs) show higher targeting for activated hepatic stellate cells (HSCs) compared to that for hepatocytes, silencing both HSP47 and HMGB1, reducing collagen secretion and liver inflammation, thereby treating fibrosis. Moreover, IPMs and FAPi-IPMs mitigate ABC effect and produce fewer PEG antibodies than LNPs, and show minimal apolipoprotein adsorption in vivo compared with LNPs, differentiating their targeting effects from LNPs. In conclusion, IPMs represent a nucleic acid delivery system with alternative targeting ability and reduced ABC effect.

Suggested Citation

  • Ziyu Zhou & Yu Feng & Mingzhou Jiang & Zijun Yao & Jing Wang & Feng Pan & Rulan Feng & Chong Zhao & Yinyu Ma & Jinge Zhou & Lei Sun & Xiaotian Sun & Changyou Zhan & Xiao He & Kuan Jiang & Jiahui Yu & , 2025. "Ionizable polymeric micelles (IPMs) for efficient siRNA delivery," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-55721-w
    DOI: 10.1038/s41467-024-55721-w
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    References listed on IDEAS

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    1. Kai Liu & Ralf Nilsson & Elisa Lázaro-Ibáñez & Hanna Duàn & Tasso Miliotis & Marie Strimfors & Michael Lerche & Ana Rita Salgado Ribeiro & Johan Ulander & Daniel Lindén & Anna Salvati & Alan Sabirsh, 2023. "Multiomics analysis of naturally efficacious lipid nanoparticle coronas reveals high-density lipoprotein is necessary for their function," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
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