<i>Panax ginseng</i> -derived Exosome-like Nanoparticles Prevent LPS-induced Septic Shock by Modulating TLR4 Glycosylation in Macrophages

Macrophages play a crucial role in the pathophysiology of sepsis, serving as central regulators of both disease onset and progression. Among the therapeutic agents investigated to modulate macrophage-driven inflammation, compounds extracted from the roots of <i>Panax ginseng</i> have been distinguished for their potent anti-inflammatory properties. Recently, attention has shifted toward ginseng-derived exosome-like nanoparticles (GDEs) because of their ability to encapsulate diverse bioactive compounds with high stability and biocompatibility. In this study, we investigated the protective effects of GDEs against lipopolysaccharide (LPS)-induced septic shock, with a particular focus on macrophage-mediated mechanisms. GDEs isolated from Korean <i>Panax ginseng</i> exhibited a spherical morphology, high stability, and effective encapsulation of bioactive ginsenosides, including Rb1, Rg1, and Rg3. GDEs significantly attenuated LPS-induced inflammatory responses in macrophages by reducing toll-like receptor 4 (TLR4) glycosylation, thereby inhibiting LPS binding. This suppression of TLR4 glycosylation led to decreased production of nitric oxide and proinflammatory cytokines (interleukin-1β, interleukin-6, and tumor necrosis factor-α), as well as inhibition of intracellular reactive oxygen species accumulation and NF-κB activation. Furthermore, GDE treatment markedly improved survival and alleviated lung, liver, and spleen damage in an LPS-induced sepsis mouse model. In summary, these findings suggest that GDEs represent a promising nanomedicine strategy for sepsis prevention, offering targeted modulation of macrophage activity without apparent adverse effects.