Endothelial-targeted modification of ginseng-derived exosomes for IL-6 SiRNA delivery ameliorates hepatic ischemia-reperfusion injury

Liver ischemia-reperfusion injury (IRI) serves as a critical pathological basis for post-hepatectomy liver failure and graft dysfunction following liver transplantation. Excessive inflammatory responses, oxidative stress, and cell death are key mechanisms underlying IRI. The lack of multi-targeted therapies contributes to the current insufficiency in clinical IRI management. This study developed endothelial-targeting VHPKQHR peptide (VHP)-modified ginseng-derived exosomes (G-Exos) loaded with IL-6 small interfering RNA (Si-IL6) (siRNA@VG-Exos) to mitigate liver IRI. VHP modification facilitated the targeted delivery of siRNA@VG-Exos to damaged endothelium, promoting their accumulation and subsequent release at the IRI site. siRNA@VG-Exos effectively reduced hepatic inflammatory cytokine release, enhanced T-SOD and CAT expression while suppressing MDA generation, thereby alleviating oxidative stress. Furthermore, they promoted the restoration of mitochondrial membrane potential, maintaining mitochondrial homeostasis. Si-IL6 additionally suppressed IL-6 expression in liver tissue, synergistically enhancing the anti-inflammatory effect of G-Exos. Moreover, siRNA@VG-Exos inhibited CD86 expression and promoted CD206 expression in hepatic macrophages, facilitating their polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype and modulating immunity. Ultimately, siRNA@VG-Exos reduced hepatic necrotic areas, lowered ALT and AST levels, and restored liver tissue function. Further sequencing analysis indicated that siRNA@VG-Exos alleviates liver IRI by inhibiting immune and inflammatory responses and oxidative stress damage. Therefore, siRNA@VG-Exos provides a novel targeted strategy for the treatment of liver IRI.