This study explored the novel mechanism of Astragaloside IV (As) in treating sepsis and its application through a biomimetic nano-delivery system (As@ZM). Sepsis, a condition of organ dysfunction caused by an abnormal host response to infection, poses a significant threat to global health due to its high mortality rate. Our findings revealed a new mechanism for As in treating sepsis, which involved the reduction of neutrophil extracellular traps (NETs) release, potentially related to As binding with IκBα to inhibit the activation of the NF-κB pathway. As treated neutrophils also improved the immune microenvironment by crosstalk with endothelial cells and lung epithelial cells. However, the stability and bioavailability of As limited its clinical application. To address this issue, we had developed a ZIF-8-based nano-delivery system that achieved targeted delivery through neutrophil membrane coating, significantly enhancing the therapeutic efficacy of As. The innovative design of As@ZM offered a new strategy for sepsis treatment, with the potential to improve clinical outcomes.