{
  "abstract": "Sepsis is a life-threatening syndrome characterized by dysregulated immune responses and metabolic dysfunction, and remains a major cause of global mortality. While nanomedicine offers new opportunities for sepsis therapy, current strategies rarely achieve comprehensive modulation of macrophage immunometabolism and microenvironmental signaling. Here, we develop a glutathione-responsive nanotherapeutic platform (EONPs) by conjugating the stimulator of interferon genes (STING) inhibitor 4-octyl itaconate to polyethylene glycol, followed by encapsulation of the dihydroorotate dehydrogenase (DHODH) inhibitor EA6. Integrated transcriptomic, metabolomic, and metagenomic analyses combined with pharmacological assessments reveal that EONPs suppress systemic hyperinflammation, reprogram macrophages toward an anti-inflammatory phenotype, restore gut microbial homeostasis, and protect against multi-organ injury in septic models. Notably, EONPs enhance the production of the microbiota-derived metabolite 5-hydroxyindoleacetic acid (5-HIAA), which is functionally linked to the anti-inflammatory response and may further support macrophage reprogramming. Our findings establish a previously unrecognized strategy for precise metabolic and microbiota-driven modulation of macrophages, offering a conceptual framework for further investigation of macrophage-targeted nanotherapeutics in sepsis.",
  "abstract_shown": true,
  "affiliations": [
    "School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, China.",
    "Laboratory of Cellular Metabolism and Precision Therapeutics, School of Life Science and Technology, Northwestern Polytechnical University, Xi'an, China.",
    "Research & Development Institute of Northwestern Polytechnical University in Shenzhen, Shenzhen, China.",
    "Department of Anesthesiology, Shanghai Key Lab of Reproduction and Development, Shanghai Key Lab of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China.",
    "Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.",
    "Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. smilejunke@imm.ac.cn.",
    "School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, China. mscheng@syphu.edu.cn.",
    "Laboratory of Cellular Metabolism and Precision Therapeutics, School of Life Science and Technology, Northwestern Polytechnical University, Xi'an, China. weigf0605@163.com.",
    "Research & Development Institute of Northwestern Polytechnical University in Shenzhen, Shenzhen, China. weigf0605@163.com."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 14,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Xintong Lu"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Wenhui Wang"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Bingjie Zhang"
    },
    {
      "affs": [
        3
      ],
      "name": "Qian Li"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Ye Chen"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Yongrui Hai"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Renming Fan"
    },
    {
      "affs": [
        4
      ],
      "name": "Shuo Fu"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Jiaxin Yan"
    },
    {
      "affs": [
        4
      ],
      "name": "Guiquan Ding"
    },
    {
      "affs": [
        0
      ],
      "name": "Zhuang Hou"
    },
    {
      "affs": [
        5
      ],
      "name": "Junke Song"
    },
    {
      "affs": [
        6
      ],
      "name": "Maosheng Cheng"
    },
    {
      "affs": [
        7,
        8
      ],
      "name": "Gaofei Wei",
      "orcid": "0000-0001-7180-7176"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/23rkpyph17vda.bib",
  "cited_by": 0,
  "doi": "10.1038/s41392-026-02947-3",
  "fulltext_url": "https://europepmc.org/articles/PMC13683383",
  "id": "23rkpyph17vda",
  "issns": [
    "2095-9907",
    "2059-3635"
  ],
  "landing_url": "https://europepmc.org/article/MED/42901916",
  "language": "eng",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "lcc",
      "QH301-705.5"
    ],
    [
      "lcc",
      "R"
    ]
  ],
  "openalex": null,
  "pdf_url": "https://europepmc.org/articles/PMC13683383?pdf=render",
  "pmcid": "PMC13683383",
  "pmid": "42901916",
  "published": "2026-10-21",
  "publisher": "Nature Publishing Group",
  "ris": "https://research.draconitic.com/paper/23rkpyph17vda.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:32Z",
      "native_id": "MED:42901916",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42901916"
    },
    {
      "first_seen": "2026-10-30T13:46:36Z",
      "native_id": "c2b034cc80c345f890cadbe337f94fd3",
      "source": "doaj",
      "url": "https://doi.org/10.1038/s41392-026-02947-3"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "lcc:QH301-705.5",
      "subfield": "general"
    },
    {
      "field": "medicine",
      "origin": "lcc:R",
      "subfield": "general"
    }
  ],
  "title": "Nanotherapeutic macrophage reprogramming through immunometabolic and microbial modulation for sepsis treatment.",
  "title_text": "Nanotherapeutic macrophage reprogramming through immunometabolic and microbial modulation for sepsis treatment.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T13:46:36Z",
  "url": "https://research.draconitic.com/paper/23rkpyph17vda",
  "venue": "Signal transduction and targeted therapy",
  "versions": []
}