As extracellular vesicles that play an active role in intercellular communication by transferring cellular materials to recipient cells, exosomes offer great potential as a natural therapeutic drug delivery vehicle. The inflammatory responses in various disease models can be attenuated through introduction of super-repressor IκB (srIκB), which is the dominant active form of IκBα and can inhibit translocation of nuclear factor κB into the nucleus. An optogenetically engineered exosome system (EXPLOR) that we previously developed was implemented for loading a large amount of srIκB into exosomes. We showed that intraperitoneal injection of purified srIκB-loaded exosomes (Exo-srIκBs) attenuates mortality and systemic inflammation in septic mouse models. In a biodistribution study, Exo-srIκBs were observed mainly in the neutrophils, and in monocytes to a lesser extent, in the spleens and livers of mice. Moreover, we found that Exo-srIκB alleviates inflammatory responses in monocytic THP-1 cells and human umbilical vein endothelial cells.

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The functional and physical interaction between mitochondria and the endoplasmic reticulum (ER) has been the subject of intense study. To test the effect of this interaction on macrophage inflammatory activation, the human macrophage‐like monocytic leukemia cell line THP‐1 was treated with oligomycin, rotenone, or sodium azide, which induce mitochondrial dysfunction (MD) by blocking the electron transport chain (ETC). MD induced by these agents triggered activation of various sensors and markers of ER stress. This linkage affected macrophage function since LPS‐induced expression of IL‐23 was enhanced by the MD inducers, and this enhancing effect was abolished by inhibition of pancreatic endoplasmic reticulum kinase (PERK) activity. This MD‐mediated ER stress may be universal since it was observed in human embryonic kidney HEK293 cells and colon cancer SW480 cells. On the other hand, MD regulated LPS‐induced activation of the AKT/GSK3β/β‐catenin pathway in a manner not affected by inhibition of PERK or inositol‐requiring enzyme 1α (IRE1α) activities. These results indicate that the occurrence of MD can lead to ER stress and these two events, separately or in combination, can affect various cellular processes.