Plant-derived extracellular vesicles deliver spermidine to reprogram macrophage metabolism and ameliorate rheumatoid arthritis.

Rheumatoid arthritis (RA) is driven by macrophage-mediated synovial inflammation closely linked to metabolic dysfunction, highlighting immunometabolism as a therapeutic target. Here, we engineered spermidine-loaded red cabbage-derived extracellular vesicles (RCEVs@SPD) as a plant-based nanoplatform to reprogram macrophage bioenergetics. In LPS-stimulated macrophages, RCEVs@SPD suppressed pro-inflammatory polarization and enhanced mitochondrial function, as evidenced by increased ATP production and mitochondrial membrane potential. Assay-based measurements further showed reduced extracellular acidification rate (ECAR) and elevated oxygen consumption rate (OCR), indicating a shift from glycolysis toward oxidative phosphorylation (OXPHOS). Untargeted LC-MS metabolomics revealed coordinated alterations in pathways supporting mitochondrial cofactor biosynthesis, redox balance, and central carbon metabolism. Transcriptomic analysis confirmed enrichment of OXPHOS and mitochondrial respiration gene signatures with concomitant repression of glycolytic programs and PI3K-AKT signaling. In vivo, RCEVs@SPD significantly alleviated collagen-induced arthritis, improved joint histopathology, and promoted anti‑inflammatory macrophage polarization. Notably, systemic macrophage depletion abolished the additional therapeutic benefit of RCEVs@SPD, demonstrating macrophage dependence. Collectively, these findings establish plant-derived extracellular vesicles as a biocompatible delivery system that potentiates spermidine to restore macrophage metabolic balance and mitigate RA pathology.