Role of chive-derived exosome-like nanoparticles in suppressing inflammation in obesity

肥胖是一种慢性进行性疾病，会导致心脏病、中风和2型糖尿病的发展，这些都是美国十大死亡原因之一。肥胖相关疾病的发生和发展与慢性低度炎症密切相关，NLRP3炎症小体是肥胖中引发炎症的关键传感器。靶向NLRP3炎症小体介导的炎症应能抑制或预防疾病进展，从而有望对抗肥胖相关疾病。然而，在肥胖患者的治疗中，尚未开发出有效且安全的特异性抑制NLRP3炎性体的策略。因此，我们研究的长期目标是开发一种新的饮食策略或治疗方式来抑制NLRP3炎症小体的活性和肥胖及肥胖相关疾病的炎症。作为第一步，该项目将确定韭菜衍生的外泌体样纳米颗粒（c - eln）在抑制肥胖炎症中的作用。我们的前期研究发现，c - eln强烈抑制原代巨噬细胞中NLRP3炎性体的激活。它们的一个生物活性分子，1,2-二吲哚油基- syn -氨基-3-磷酸胆碱，被鉴定为NLRP3炎症小体的抑制剂。在C57BL/6J小鼠中，口服c - eln，同时开始饲喂高脂饮食，可降低NLRP3炎性体活性，改善代谢健康。在我们初步工作的基础上，本项目将验证c - eln含有抑制NLRP3炎症小体活性和改善肥胖炎症的活性生物分子的中心假设。这一假设将通过两个特定目标进行验证：1)确定c - eln中抑制NLRP3炎症小体活性的活性生物分子；2)确定c - eln及其活性生物分子在抑制肥胖炎症中的作用。本研究的成功完成是将c - eln和活性生物分子转化为抑制NLRP3炎性体活性和肥胖炎症的干预措施的第一步。利用膳食eln靶向NLRP3炎性体是一种创新的方法。膳食eln的独特特性，包括组织生物利用度、生物活性、生物分子保护和传递，以及它们在可食用植物中的丰富程度，赋予了它们很高的转化潜力。

Obesity is a chronic progressive disease that leads to the development of heart disease, stroke, and type 2 diabetes, which are among the top ten leading causes of death in the United States. The initiation and progression of obesity-related diseases is strongly associated with chronic low-grade inflammation, and the NLRP3 inflammasome is a key sensor that instigates inflammation in obesity. Targeting NLRP3 inflammasome-mediated inflammation should curb or prevent the disease progression and thus holds therapeutic promise to combat obesity-related diseases. However, effective and safe strategies that specifically inhibit the NLRP3 inflammasome in obesity have not been developed for patient treatment. As such, the long- term goal of our research is to develop a new dietary strategy or therapeutic modality to suppress NLRP3 inflammasome activity and inflammation in obesity and obesity-related diseases. As an initial step, this project will define the role of chive-derived exosome-like nanoparticles (C-ELNs) in suppressing inflammation in obesity. Our pilot studies found that C-ELNs strongly inhibited NLRP3 inflammasome activation in primary macrophages. One of their bioactive molecules, 1,2-dilinoleoyl-sn-glcyero-3-phosphocholine, was identified as an inhibitor of the NLRP3 inflammasome. Oral administration of C-ELNs, started concomitantly with high-fat diet feeding, reduced NLRP3 inflammasome activity and improved metabolic health in the C57BL/6J mice. Building on our preliminary work, this project will test the central hypothesis that C-ELNs contain active biomolecules that inhibit NLRP3 inflammasome activity and ameliorate inflammation in obesity. This hypothesis will be tested through two specific aims: 1) identify active biomolecules in C-ELNs that inhibit NLRP3 inflammasome activity and 2) define the role of C-ELNs and their active biomolecules in suppressing inflammation in obesity. Successful completion of the proposed research be the first step toward the translation of C-ELNs and active biomolecules into an intervention to suppress NLRP3 inflammasome activity and inflammation in obesity. Utilizing dietary ELNs to target the NLRP3 inflammasome is an innovative approach. The unique features of dietary ELNs, including tissue bioavailability, bioactivity, and biomolecule protection and delivery, as well as their abundance in edible plants confer upon them high translational potential.