Exosome-based delivery of super-repressor IκBα relieves sepsis-associated organ damage and mortality

Abstract

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.

Extracellular vesicle–encapsulated IL-10 as novel nanotherapeutics against ischemic AKI

“…IL-10 is a potential therapeutic candidate for multiple diseases; however, its clinical translation is severely hindered by its short half-life and off-target effects ( 3 ). Recently, because of their great versatility, low immunogenicity, and favorable safety profile, EVs have attracted considerable attention as drug delivery vehicles for various protein therapeutics, such as IL-4 ( 28 ) and IκBα (inhibitor of nuclear factor κBα) ( 29 ). Thus, we attempted to develop a EV-based nanotherapeutic to improve the pharmacokinetic properties of IL-10.…”

Post-translational Modifications of IκBα: The State of the Art

“…The IκBα-super repressor (IκBα-SR), a mutant form of IκBα, which can neither be phosphorylated nor ubiquitinated, is found to inhibit NF-κB activation. Furthermore, the intraperitoneal injection of purified IκBα-SR-loaded exosomes attenuates mortality and systemic inflammation in septic mouse models ( Choi et al, 2020 ). IκBα-SR can also increase the sensitivity of pancreatic cancer and pancreatic ductal adenocarcinoma to chemotherapeutics and inhibit tumor development in hepatitis-related cancer murine models ( Sato et al, 2003 ; Pikarsky et al, 2004 ; Waters et al, 2015 ).…”

Platelet-rich Plasma Enhanced MSCs Repair for Glycerin-induced Acute Kidney Injury via AKT/Rab27 Paracrine Pathway

“…Exosomes, one form of extracellular vesicles, have potential as mediators of intercellular message and play a major role in cell-to-cell communication, while therapeutic effects of human MSC-derived exosomes have been veri ed using a rodent model [21,37,38] . And then research team nding platelet-rich plasma improved the wound healing potential of mesenchymal stem cells through paracrine and metabolism alterations [39] .…”