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

肥胖是一种慢性进行性疾病，导致心脏病、中风和2型糖尿病的发展，这些疾病是美国十大主要死亡原因之一。肥胖相关疾病的发生和进展与慢性低度炎症密切相关，NLRP 3炎性小体是引发肥胖炎症的关键传感器。靶向NLRP 3炎性体介导的炎症应抑制或预防疾病进展，从而具有对抗肥胖相关疾病的治疗前景。然而，特异性抑制肥胖症中的NLRP 3炎性小体的有效且安全的策略尚未开发用于患者治疗。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肥胖和肥胖相关疾病中的NLRP 3炎性体活性和炎症。作为第一步，该项目将定义韭菜衍生的外泌体样纳米颗粒（C-ELN）在抑制肥胖症炎症中的作用。我们的初步研究发现，C-ELN强烈抑制原代巨噬细胞中的NLRP 3炎性小体活化。它们的生物活性分子之一，1，2-二亚油酰基-sn-甘油-3-磷酸胆碱，被鉴定为NLRP 3炎性体的抑制剂。C-ELN的口服给药，伴随高脂肪饮食喂养开始，降低了NLRP 3炎性小体活性，改善了C57 BL/6 J小鼠的代谢健康。基于我们的初步工作，该项目将测试中心假设，即C-ELN含有抑制NLRP 3炎性体活性并改善肥胖症炎症的活性生物分子。该假设将通过两个特定目的进行测试：1）鉴定C-ELN中抑制NLRP 3炎性体活性的活性生物分子，和2）定义C-ELN及其活性生物分子在抑制肥胖症炎症中的作用。这项研究的成功完成是将C-ELN和活性生物分子转化为干预措施以抑制NLRP 3炎性体活性和肥胖症炎症的第一步。利用膳食ELN靶向NLRP 3炎性体是一种创新方法。膳食ELN的独特特征，包括组织生物利用度、生物活性和生物分子保护和递送，以及它们在可食用植物中的丰富度赋予它们高的翻译潜力。

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.