Rosa damascena-Derived Nanovesicles Restore GAS6-driven Efferocytic Balance in LPS-Induced Inflammatory Model

Resolution of inflammation is an active, tightly regulated process, and its dysregulation contributes to acute and chronic inflammatory diseases. This study investigated the anti-inflammatory and pro-resolving effects of Rosa damascena-derived nanovesicles (RD-NVs), with particular emphasis on efferocytosis. RD-NVs were isolated by ultracentrifugation and characterized using dynamic light scattering, nanoparticle tracking analysis, zeta potential analysis, and electron microscopy. The nanoparticles exhibited spherical morphology, an average diameter of approximately 212 nm, and a zeta potential of approximately -40 mV, indicating good colloidal stability. RD-NVs were biocompatible with RAW264.7 macrophages and significantly reduced intracellular reactive oxygen species (68.48% and 41.18%) while restoring mitochondrial membrane potential (90.80% and 93.82%) in LPS-stimulated cells. They also downregulated TNF-α and HMGB1 expression while restoring GAS6 expression in a dose-dependent manner, supporting enhanced efferocytosis and inflammation resolution. Western blotting confirmed GAS6 restoration, and reduced HMGB1 suggested diminished secondary necrosis. Biodistribution studies showed preferential accumulation in the liver and spleen. In vivo, RD-NVs significantly attenuated LPS-induced paw edema, reduced leukocyte infiltration, and suppressed TNF-α expression. These findings demonstrate that RD-NVs promote inflammation resolution through restoration of GAS6-associated efferocytosis, mitochondrial protection, and suppression of inflammatory mediators, highlighting their potential as plant-derived resolution-oriented nanotherapeutics.