基于TLR4信号轴的Exosomes仿生体构建及狼疮性肾炎治疗机制研究

Mesenchymal stem cells (MSCs) Exosomes (Exo) have immunomodulatory and anti-inflammatory ability in the treatment of autoimmune diseases that is considered to have great potential, but due to the limited quantity of Exosomes secreted by mammalian cells and off-targeting and inferior pharmacokinetic properties is a major impediment for their applications in nanomedicine of clinical application. It has been shown that the advantages of multi-target therapy and TLR4 signal axis are the effective targets for treatment with lupus nephropathy (LN). This project will study on the base of research about yield sufficient quantity of Exosomes as the biological carrier drug delivery system. We will try to modify lipsomes by targeting and membrane fusion peptide with (KKEEE)3K while adopting the concept of Targeted Drug Delivery System (TDDS). The modified liposomes will package two kind of drugs which plays a role in TLR4 signaling pathway on HMGB1 siRNA and dihydroarteannuin (DHA), then loaded on EMs by the previously constructed liposomes, to build a new endogenous biological drug delivery system, which can realize the different targets of small molecule drugs and gene drugs with high drug loading, total package, and can avoid the liver first pass effect, prolong the circulation of blood in the body, and can retain the beginning of immunological characteristics of Exo. The related research will explore the renal lesion precise targeting and multi-angle regulation of LN under the pathological condition and the feasibility synergy mechanism to rectify immune disorder. Construction of this new multi-functional targeted vehicle based on Exosome mimetics (EMs) will expand the research area of TDDS, which has scientific significance and shows innovation. This new vehicle has promising prospect and it will promote the development of targeted therapy on treatment of autoimmune diseases with the joint of many subjects.

间充质干细胞（MSCs）的Exosomes（Exo）具有免疫调节和抗炎能力，在自身免疫性疾病的治疗中具有巨大的潜力，但由于自然分泌的Exo有限，且靶向性和体内药动学差，难以应用于临床。已研究表明狼疮性肾病（LN）多靶点治疗的优势及TLR4信号轴为抗LN药物的靶点。本项目将在课题组已获得高产Exo仿生体（EMs）作为药物载体研究的基础上，尝试以靶向药物递送系统的理念，通过靶向和膜融合兼具的肽段(KKEEE)3K修饰并携带作用于TLR4信号轴上HMGB1的siRNA和双氢青蒿素（DHA）的脂质体共负载于EMs，拟构建新型的内源性生物载体，既能实现对多种药物的高载药量、共包裹，又能避免肝首过效应，改善药动学特性，并保留Exo自身的免疫特性。研究将探索肾脏病变部位精准靶向、多维度调节LN病理状态下免疫紊乱的可行性和协同作用机制，为拓展内源性给药载体的研究领域和治疗自免疫性疾病提供创造性的研究思路。

狼疮性肾炎（LN）是SLE的主要并发症和死亡原因。目前临床上尚无有效根治方案，主要用糖皮质激素、免疫抑制剂进行治疗，副作用大，难以坚持长期给药。因此，积极探寻安全有效新的治疗方法、治疗药物并明确其作用机理仍是一项紧迫的任务。已研究表明多靶点治疗（Multi-target therapy）LN是行之可效的方法。.我们的研究发现，TLR4信号通路过度激活与 SLE 的活动及 LN 的发生发展关系密切。我们的研究构建了基于TLR4信号通路多功能载药多种纳米递送系统的构建及表征；进行了体外作用效果评价；对狼疮性肾炎（LN）的治疗效果评价；对TLR4信号通路的作用及机制评价等等；以TDDS的理念，构建了全新的治疗自身免疫性疾病内源性的生物给药载体，拓展TDDS的研究领域，并结合安全性评价，全面评估几种纳米生物载体的可行性及其针对LN的治疗前景，既能实现了对多种药物的高载药量、共包裹，又能避免肝首过效应，改善药动学特性。并尝试开展了间充质干细胞的外泌体为载体材料研究，将探索肾脏病变部位精准靶向、多维度调节了LN病理状态下免疫紊乱的可行性和协同作用机制，为不仅具有重要的科学意义，体现了创新性，也具有很好的应用前景。