Nanotherapeutic Macrophage Reprogramming through Immunometabolic and Microbial Modulation for Sepsis Treatment

Sepsis is a life-threatening syndrome characterized by dysregulated immune responses and metabolic dysfunction, and remains a major cause of global mortality. While nanomedicine has shown promise in targeting inflammatory pathways, current strategies often fail to comprehensively modulate the complex immunometabolic and microenvironmental networks that regulate macrophage function during sepsis. To address this challenge, 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. Through integrated transcriptomic, metabolomic, and metagenomic profiling combined with comprehensive in vitro and in vivo pharmacological assessments, we demonstrate that EONPs suppress systemic hyperinflammation, reprogram macrophages toward an anti-inflammatory phenotype, restore gut microbial homeostasis, and protect against multi-organ dysfunction in sepsis models. Notably, we identify that EONPs enhance the production of the microbiota-derived metabolite 5-hydroxyindoleacetic acid (5-HIAA), which synergistically reinforces macrophage immunometabolic reprogramming. Our findings establish a previously unrecognized strategy for precise immunometabolic and microbiota-driven modulation of macrophages, offering a new conceptual framework for advancing nanotherapeutic interventions in sepsis.脓毒症（Sepsis）是一类以免疫应答失调与代谢功能障碍为特征的致死性综合征，目前仍是全球致死的主要诱因之一。尽管纳米医学在靶向炎症通路方面已展现出应用潜力，但现有治疗策略往往无法全面调控脓毒症期间调控巨噬细胞功能的复杂免疫代谢与微环境网络。为解决这一难题，我们开发了一种谷胱甘肽响应型纳米治疗平台（EONPs）：将干扰素基因刺激因子（STING）抑制剂4-辛基衣康酸与聚乙二醇结合，随后包载二氢乳清酸脱氢酶（DHODH）抑制剂EA6。通过整合转录组学、代谢组学与宏基因组学表征，并结合全面的体外与体内药理学评价，我们证实EONPs可抑制脓毒症模型中的全身炎症反应亢进，将巨噬细胞重编程为抗炎表型，恢复肠道微生物稳态，并抵御多器官功能障碍。值得注意的是，我们发现EONPs可促进菌群衍生代谢物5-羟吲哚乙酸（5-HIAA）的产生，该物质可协同增强巨噬细胞的免疫代谢重编程。本研究确立了一种此前未被报道的精准免疫代谢与菌群介导的巨噬细胞调控策略，为推进脓毒症领域的纳米治疗干预提供了全新的概念框架。