Extracellular vesicles (EVs) function in many physiological events ranging from normal cellular activity to pathogenic processes. Some EVs prepared in vitro have exhibited therapeutic effects in preclinical models of immune or neurodegenerative disease. In a recent study, researchers generated EVs enriched with HSPB8 (small heat shock protein B8) in vitro from oligodendroglia (OLs). HSPB8 protects cells from oxidative stress-mediated cell death by supporting autophagic activity and could be carried by EVs. Both the native OL-EVs and the HSPB8-enriched OL-EVs were internalized by a microglial cell line and primary mixed neural cultures without inducing cell death. The HSPB8-enriched OL-EVs increased the endogenous production of HSPB8 mRNA. Both EV subsets helped maintain cellular homeostasis during chronic inflammation by increasing autophagic vesicle formation. In cells under oxidative stress, both subsets of EVs reduced levels of ubiquitinated protein, reactive oxygen species, and mitochondrial depolarization, but the HSPB8-enriched OL-EVs exhibited stronger protective effects. This study demonstrated that HSPB8-enriched OL-EVs could play a better protective role than native OL-EVs and that further development of engineered OL-derived EVs could lead to novel therapeutics for chronic inflammation.