Targeting the NR1D1–IGF2BP2–V‐ATPase Axis With Hybrid Nanovesicles Restores Macrophage Rhythms to Reverse Sepsis‐Induced Immunosuppression

Patients with sepsis exhibit circadian disruption and persistent immunosuppression. However, the molecular mechanisms linking them remain unclear. Integration of multi‐cohort transcriptomic and single‐cell datasets shows that circadian gene dysregulation in patients with sepsis and septic mice correlates with disease severity and immunosuppressive states, with monocytes/macrophages emerging as a principal affected population. Sustained endotoxin stimulation elevates the core clock repressor NR1D1 in macrophages, which occupies the Igf2bp2 promoter and suppresses its transcription. Loss of IGF2BP2 destabilizes the V‐ATPase subunit transcripts Atp6v1b2 and Atp6v0c through an m 6 A‐dependent mechanism, disrupting phagolysosomal acidification rhythms and pathogen clearance. siRNA‐mediated NR1D1 knockdown restores IGF2BP2 expression, circadian oscillations, and phagolysosomal function during the development of endotoxin tolerance. To achieve therapeutic delivery, we engineer hybrid membrane nanovesicles (siNR1D1@HM‐LNP) that reverse circadian and immune dysregulation in septic mice, enhance bacterial clearance, and markedly improve survival. These findings establish an NR1D1‐mediated circadian‐immune coupling mechanism and provide a therapeutic strategy for targeting sepsis‐induced immunosuppression. Sepsis disrupts immune‐cell rhythms and weakens bacterial clearance. Biomimetic nanovesicles combining erythrocyte and inflammation‐activated macrophage membranes deliver siNR1D1 to dysfunctional macrophages, restoring the NR1D1–IGF2BP2–V‐ATPase pathway, circadian regulation, phagolysosomal acidification, and antimicrobial defense. In mouse models of polymicrobial sepsis and secondary pneumonia, treatment improves immune balance and bacterial control, reduces organ injury, and increases survival.