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Biomimetic nanoparticles deliver mRNAs encoding costimulatory receptors and enhance T cell mediated cancer immunotherapy

Author

Listed:
  • Wenqing Li

    (The Ohio State University)

  • Xinfu Zhang

    (The Ohio State University
    Dalian University of Technology)

  • Chengxiang Zhang

    (The Ohio State University)

  • Jingyue Yan

    (The Ohio State University)

  • Xucheng Hou

    (The Ohio State University)

  • Shi Du

    (The Ohio State University)

  • Chunxi Zeng

    (The Ohio State University)

  • Weiyu Zhao

    (The Ohio State University)

  • Binbin Deng

    (The Ohio State University)

  • David W. McComb

    (The Ohio State University
    The Ohio State University)

  • Yuebao Zhang

    (The Ohio State University)

  • Diana D. Kang

    (The Ohio State University)

  • Junan Li

    (The Ohio State University)

  • William E. Carson

    (The Ohio State University Wexner Medical Center and The OSU James Comprehensive Cancer Center)

  • Yizhou Dong

    (The Ohio State University
    The Ohio State University
    The Ohio State University
    The Ohio State University)

Abstract

Antibodies targeting costimulatory receptors of T cells have been developed for the activation of T cell immunity in cancer immunotherapy. However, costimulatory molecule expression is often lacking in tumor-infiltrating immune cells, which can impede antibody-mediated immunotherapy. Here, we hypothesize that delivery of costimulatory receptor mRNA to tumor-infiltrating T cells will enhance the antitumor effects of antibodies. We first design a library of biomimetic nanoparticles and find that phospholipid nanoparticles (PL1) effectively deliver costimulatory receptor mRNA (CD137 or OX40) to T cells. Then, we demonstrate that the combination of PL1-OX40 mRNA and anti-OX40 antibody exhibits significantly improved antitumor activity compared to anti-OX40 antibody alone in multiple tumor models. This treatment regimen results in a 60% complete response rate in the A20 tumor model, with these mice being resistant to rechallenge by A20 tumor cells. Additionally, the combination of PL1-OX40 mRNA and anti-OX40 antibody significantly boosts the antitumor immune response to anti-PD-1 + anti-CTLA-4 antibodies in the B16F10 tumor model. This study supports the concept of delivering mRNA encoding costimulatory receptors in combination with the corresponding agonistic antibody as a strategy to enhance cancer immunotherapy.

Suggested Citation

  • Wenqing Li & Xinfu Zhang & Chengxiang Zhang & Jingyue Yan & Xucheng Hou & Shi Du & Chunxi Zeng & Weiyu Zhao & Binbin Deng & David W. McComb & Yuebao Zhang & Diana D. Kang & Junan Li & William E. Carso, 2021. "Biomimetic nanoparticles deliver mRNAs encoding costimulatory receptors and enhance T cell mediated cancer immunotherapy," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27434-x
    DOI: 10.1038/s41467-021-27434-x
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    Cited by:

    1. Zhaoting Li & Fanyi Mo & Yixin Wang & Wen Li & Yu Chen & Jun Liu & Ting-Jing Chen-Mayfield & Quanyin Hu, 2022. "Enhancing Gasdermin-induced tumor pyroptosis through preventing ESCRT-dependent cell membrane repair augments antitumor immune response," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Zhijian Li & Laura Amaya & Ruoxi Pi & Sean K. Wang & Alok Ranjan & Robert M. Waymouth & Catherine A. Blish & Howard Y. Chang & Paul A. Wender, 2023. "Charge-altering releasable transporters enhance mRNA delivery in vitro and exhibit in vivo tropism," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    3. Abigail R. Gress & Christine E. Ronayne & Joshua M. Thiede & David K. Meyerholz & Samuel Okurut & Julia Stumpf & Tailor V. Mathes & Kenneth Ssebambulidde & David B. Meya & Fiona V. Cresswell & David R, 2023. "Recently activated CD4 T cells in tuberculosis express OX40 as a target for host-directed immunotherapy," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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