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.