Nanotherapeutic macrophage reprogramming through immunometabolic and microbial modulation for sepsis treatment.
9 affiliations
- 1School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, China.
- 2Laboratory of Cellular Metabolism and Precision Therapeutics, School of Life Science and Technology, Northwestern Polytechnical University, Xi'an, China.
- 3Research & Development Institute of Northwestern Polytechnical University in Shenzhen, Shenzhen, China.
- 4Department 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.
- 5Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
- 6Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. [email protected].
- 7School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, China. [email protected].
- 8Laboratory of Cellular Metabolism and Precision Therapeutics, School of Life Science and Technology, Northwestern Polytechnical University, Xi'an, China. [email protected].
- 9Research & Development Institute of Northwestern Polytechnical University in Shenzhen, Shenzhen, China. [email protected].
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.
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BibTeX
@article{lu2026nanotherapeutic,
title = {{Nanotherapeutic macrophage reprogramming through immunometabolic and microbial modulation for sepsis treatment.}},
author = {Xintong Lu and Wenhui Wang and Bingjie Zhang and Qian Li and Ye Chen and Yongrui Hai and Renming Fan and Shuo Fu and Jiaxin Yan and Guiquan Ding and Zhuang Hou and Junke Song and Maosheng Cheng and Gaofei Wei},
journal = {Signal transduction and targeted therapy},
year = {2026},
month = oct,
doi = {10.1038/s41392-026-02947-3},
url = {https://europepmc.org/article/MED/42901916},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Nanotherapeutic macrophage reprogramming through immunometabolic and microbial modulation for sepsis treatment.
AU - Xintong Lu
AU - Wenhui Wang
AU - Bingjie Zhang
AU - Qian Li
AU - Ye Chen
AU - Yongrui Hai
AU - Renming Fan
AU - Shuo Fu
AU - Jiaxin Yan
AU - Guiquan Ding
AU - Zhuang Hou
AU - Junke Song
AU - Maosheng Cheng
AU - Gaofei Wei
PY - 2026
DA - 2026/10/21
JO - Signal transduction and targeted therapy
DO - 10.1038/s41392-026-02947-3
UR - https://europepmc.org/article/MED/42901916
AB - 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.
SN - 2095-9907
SN - 2059-3635
ER -