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

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 Zhang, Raobo Xu, Jun Yan, Michael L. Merchant, Craig J. McClain and Huang-Ge Zhang ()
Additional contact information
Yun Teng: University of Louisville School of Medicine
Chao Luo: University of Louisville School of Medicine
Xiaolan Qiu: University of Louisville School of Medicine
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
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
Jae Yeon Hwang: University of Louisville School of Medicine
Maiying Kong: University of Louisville School of Medicine
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

Nature Communications, 2025, vol. 16, issue 1, 1-25

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-56498-2

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