Disordered coagulation is an independent risk factor for mortality in patients with sepsis and currently lacks effective therapeutic strategies. In this study, PIM1, a novel target predominantly expressed in macrophages during sepsis, is investigated by bioinformatics analysis and clinical evaluation in patients with sepsis compared with healthy individuals. The regulatory mechanism by which PIM1 promotes the release of tissue factors (TF) from macrophages by modulating the phosphorylation levels of mTOR through the AKT and MAPK signaling pathways is demonstrated both in vitro and in vivo. Based on these findings, a multifunctional co-delivery system based on mesoporous polydopamine (MPDA) nanoparticles (NPs) coated with cationic polyethyleneimine (PEI) and macrophage-targeting glucomannan (GM) (MPDA@PEI@GM NPs) is proposed for the co-delivery of the PIM1 inhibitors SMI-4a and small interfering RNA (siPIM1) to downregulate PIM1 expression and improve sepsis-induced coagulopathy. MPDA@SMI-4a@PEI/siPIM1@GM demonstrates negligible cytotoxicity, excellent macrophage-targeting efficiency, prolonged blood circulation, and significantly downregulated PIM1 expression. Notably, treatment with MPDA@SMI-4a@PEI/siPIM1@GM improves the survival rates of septic mice by ameliorating disordered coagulation and alleviating lung injury. Bioinformatic analysis and clinical research-guided MPDA@SMI-4a@PEI/siPIM1@GM co-delivery systems improve TF-mediated coagulopathy in sepsis and alleviate sepsis-induced acute lung injury, marking a significant advancement in the development of clinical antisepsis therapies.