Treatment of sepsis with exosome-based delivery of super-repressor IκBα

Abstract

Sepsis is a complex condition characterized by paradoxical host immune responses to infection. The heterogeneous pathophysiology of sepsis, involving dysregulated systemic inflammatory response and multiple organ failure, has required the development of new breakthroughs in therapeutics. Exosomes are extracellular vesicles that are secreted by almost all cells and play an active role in intercellular communication by transferring a variety of cellular materials, such as proteins and nucleic acids, to recipient cells. With their ability to deliver various cargoes and cross biological barriers, 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 kappa-B (NF-κB) into the nucleus, even in the presence of pro-inflammatory stimulation. An optogenetically engineered exosome system (EXPLOR) was applied for loading a large amount of srIκB into exosomes in stably transfected cells. I showed that intraperitoneal injection of purified srIκB-loaded exosomes (Exo-srIκBs) attenuates mortality, organ damage and systemic inflammation in septic mouse models. In a biodistribution study using exosomes labeled with fluorescence dye, Exo-srIκBs were mainly observed in the neutrophils, and in monocytes to a lesser extent, in the spleens and livers of mice. Moreover, I found that Exo-srIκB alleviates inflammatory responses in monocytic THP-1 cells and human umbilical vein endothelial cells (HUVECs) in response to lipopolysaccharide (LPS) or tumor necrosis factor (TNF)-α. These results suggest that Exo-srIκB can protect against systemic inflammation and sepsis-induced death by inhibiting NF-κB activation.