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Plant-nanoparticles enhance anti-PD-L1 efficacy by shaping human commensal microbiota metabolites

Author

Listed:
  • Yun Teng

    (University of Louisville School of Medicine)

  • Chao Luo

    (University of Louisville School of Medicine
    Huai’an)

  • Xiaolan Qiu

    (University of Louisville School of Medicine
    Huai’an)

  • Jingyao Mu

    (University of Louisville School of Medicine)

  • Mukesh K. Sriwastva

    (University of Louisville School of Medicine)

  • Qingbo Xu

    (University of Louisville)

  • Minmin Liu

    (University of Louisville School of Medicine
    Huai’an)

  • Xin Hu

    (University of Texas MD Anderson Cancer Center)

  • Fangyi Xu

    (University of Louisville School of Medicine)

  • Lifeng Zhang

    (University of Louisville School of Medicine)

  • Juw Won Park

    (University of Louisville School of Medicine
    University of Louisville)

  • Jae Yeon Hwang

    (University of Louisville School of Medicine)

  • Maiying Kong

    (University of Louisville School of Medicine
    University of Louisville)

  • Zhanxu Liu

    (University of Louisville School of Medicine)

  • Xiang Zhang

    (University of Louisville)

  • Raobo Xu

    (University of Louisville)

  • Jun Yan

    (University of Louisville School of Medicine)

  • Michael L. Merchant

    (University of Louisville)

  • Craig J. McClain

    (University of Louisville School of Medicine)

  • Huang-Ge Zhang

    (University of Louisville School of Medicine
    University of Louisville
    Robley Rex Veterans Affairs Medical Center)

Abstract

Diet has emerged as a key impact factor for gut microbiota function. However, the complexity of dietary components makes it difficult to predict specific outcomes. Here we investigate the impact of plant-derived nanoparticles (PNP) on gut microbiota and metabolites in context of cancer immunotherapy with the humanized gnotobiotic mouse model. Specifically, we show that ginger-derived exosome-like nanoparticle (GELN) preferentially taken up by Lachnospiraceae and Lactobacillaceae mediated by digalactosyldiacylglycerol (DGDG) and glycine, respectively. We further demonstrate that GELN aly-miR159a-3p enhances anti-PD-L1 therapy in melanoma by inhibiting the expression of recipient bacterial phospholipase C (PLC) and increases the accumulation of docosahexaenoic acid (DHA). An increased level of circulating DHA inhibits PD-L1 expression in tumor cells by binding the PD-L1 promoter and subsequently prevents c-myc-initiated transcription of PD-L1. Colonization of germ-free male mice with gut bacteria from anti-PD-L1 non-responding patients supplemented with DHA enhances the efficacy of anti-PD-L1 therapy compared to controls. Our findings reveal a previously unknown mechanistic impact of PNP on human tumor immunotherapy by modulating gut bacterial metabolic pathways.

Suggested Citation

  • Yun Teng & Chao Luo & Xiaolan Qiu & Jingyao Mu & Mukesh K. Sriwastva & Qingbo Xu & Minmin Liu & Xin Hu & Fangyi Xu & Lifeng Zhang & Juw Won Park & Jae Yeon Hwang & Maiying Kong & Zhanxu Liu & Xiang Zh, 2025. "Plant-nanoparticles enhance anti-PD-L1 efficacy by shaping human commensal microbiota metabolites," Nature Communications, Nature, vol. 16(1), pages 1-25, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56498-2
    DOI: 10.1038/s41467-025-56498-2
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    References listed on IDEAS

    as
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