<p>Sepsis is a prominent cause of mortality worldwide, attributed to the overactivation of the immune system. Ginseng is a medicinal plant with strong biological effects, yet the mechanism underlying its limited bioavailability and robust biological activity remains poorly understood. Here, our data revealed that ginseng-derived vesicle-like nanoparticles (GDVLNs) exhibit high biocompatibility and can be rapidly absorbed and distributed to various extraintestinal organs. Moreover, GDVLNs effectively protect against multiple organ dysfunction caused by sepsis in an RNA-dependent manner, as evidenced by the retention of protection after protein degradation, but loss of protective effect following lipid extraction administration and RNA degradation. Furthermore, through de novo miRNA sequencing, we identified pgi-MIR6136a-p3 as the most abundant species-specific miRNA in GDVLNs. We found that GDVLNs deliver pgi-MIR6136a-p3 into macrophages, thereby alleviating sepsis-induced multiple organ injury. Mechanistically, pgi-MIR6136a-p3 derived from GDVLNs inhibits systemic inflammation against sepsis by directly targeting ELF3 and suppressing the activation of the NF-κB signaling. Lastly, we validated that GDVLNs-derived pgi-MIR6136a-p3 also suppresses ELF3/NF-κB signaling in human monocyte-derived macrophages. These findings reveal a novel molecular mechanism that GDVLNs derived pgi-MIR6136a-p3 regulate innate immunity across kingdoms and provide a promising translational therapeutic strategy for sepsis.</p> Graphical abstract <p></p>