Therapeutic Potential of Plant-Derived Small Extracellular Vesicles in Sepsis: A Network Meta-analysis.

Sepsis is a life-threatening condition characterized by systemic inflammation and multi-organ dysfunction. Plant-derived small extracellular vesicles (sEVs) have emerged as promising therapeutic agents due to their antioxidant, anti-inflammatory, and immunomodulatory properties. This study conducted a network meta-analysis to identify the most effective plant-derived sEVs for reducing sepsis-induced inflammation and oxidative stress. The analysis included 13 studies evaluating 10 plant-derived sEVs in sepsis-mimicking conditions, with primary outcomes focused on cytokine levels and reactive oxygen species (ROS) production in vitro and in vivo. Secondary outcomes included nuclear factor erythroid 2-related factor 2 (Nrf2) expression and cell viability. The study protocol was registered with PROSPERO (CRD420251011005). Ginger-derived sEVs were identified as the most effective, significantly reducing pro-inflammatory cytokines (interleukin-6 and tumor necrosis factor-α), increasing the anti-inflammatory cytokine (interleukin-10), and suppressing ROS production. They also enhanced Nrf2 expression and improved cell viability, highlighting their role in antioxidant defense and cytoprotection. In conclusion, ginger-derived sEVs are the most effective plant-derived sEVs for mitigating sepsis-induced inflammation and oxidation in both in vitro and in vivo sepsis-mimicking models.