Single-cell analysis of the decidua unveils the mechanism of anti-inflammatory exosomes for chorioamnionitis in nonhuman primates.

Abstract

The effectiveness of exosomes engineered to carry a dominantly active variant of inhibitor α of nuclear factor κB (NF-κB) (IκBα), super-repressor IκB (srIκB), that inhibits the expression of NF-κB in various animal models of inflammatory diseases has been demonstrated. In this study, we used a lipopolysaccharide (LPS)-induced chorioamnionitis model in pregnant nonhuman primates to explore the therapeutic potential and mode of action of srIκB-loaded exosomes (Exo-srIκBs). Intraamniotic injection of LPS induced infiltration of BCL2A1-positive neutrophils and CD68-positive macrophages in the extraplacental membranes, causing fetal lung injury. Conversely, administration of Exo-srIκB via intraamniotic and intravenous routes (6.9 × 10¹⁰ and 4 × 10¹¹ particle numbers, respectively) ameliorated these effects. Single-cell RNA sequencing of the decidua and bulk RNA sequencing of the choriodecidua highlighted that Exo-srIκB treatment mitigated LPS-induced inflammatory pathways, particularly in macrophages, leading to a cascade effect on neutrophils through NF-κB signaling inhibition. These findings underscore the potential of Exo-srIκB as a therapeutic strategy for chorioamnionitis.