Jang Seung Hyun, Choi Hojun, Lee Eun Mi, Yoon Seung-Bin, Kim Hye-Jung, Park Cheolhyoung, Won Jae Kyung, Shin Seung Han, Kim Ji-Su, Park Chan-Wook, Gee Heon Yung, Choi Chulhee
Department of Pharmacology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Korea.
ILIAS Biologics Inc., Daejeon, Korea.
Sci Adv. 2025 Jul 4;11(27):eadp0467. doi: 10.1126/sciadv.adp0467. Epub 2025 Jul 2.
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 × 10 and 4 × 10 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.
经工程改造携带核因子κB（NF-κB）抑制因子α（IκBα）的显性活性变体——超级抑制因子IκB（srIκB）的外泌体，已在多种炎症性疾病动物模型中证明其对NF-κB表达具有抑制作用。在本研究中，我们使用脂多糖（LPS）诱导的孕非人类灵长类动物绒毛膜羊膜炎模型，来探索装载srIκB的外泌体（Exo-srIκBs）的治疗潜力和作用模式。羊膜腔内注射LPS会导致胎盘外膜中BCL2A1阳性中性粒细胞和CD68阳性巨噬细胞浸润，从而引起胎儿肺损伤。相反，通过羊膜腔和静脉途径分别给予Exo-srIκB（颗粒数分别为6.9×10和4×10）可改善这些影响。对蜕膜进行单细胞RNA测序以及对绒毛膜蜕膜进行整体RNA测序结果表明，Exo-srIκB治疗可减轻LPS诱导的炎症途径，尤其是在巨噬细胞中，通过抑制NF-κB信号传导对中性粒细胞产生级联效应。这些发现强调了Exo-srIκB作为绒毛膜羊膜炎治疗策略的潜力。
