Development of chronic pain is related to aberrant neuroimmune signaling. Small extracellular vesicles (sEVs) are 30-150nm size particles of endosomal origin. They play an important role in neuroimmune crosstalk facilitating transfer of biomolecular cargo between cells. Our studies show that sEVs from RAW 264.7 macrophage cells can be therapeutic or prophylactic in mouse model of inflammatory pain. We investigated the mechanistic basis of how sEVs from lipopolysaccharide (LPS) stimulated (Exo+) and unstimulated (Exo-) cells impact primary glial cells, dendritic cells (DCs) and adaptive immune cells such as CD4 T cells. We hypothesize that macrophage derived sEVs can potentiate T cell activation directly, or indirectly by the upregulation of major histocompatibility complex-II (MHC-II) and co-stimulatory molecules on DCs, attenuating pain hypersensitivity. We will also test if sEVs confer protection to glial cells in the context of inflammation.