基于SR-B1/NRP1受体协同靶向LSEC的仿生性纳米载体构建及其抗肝纤维化应用

肝血窦内皮细胞（LSEC）是肝脏免疫稳态的重要“守护者”，NO合成受阻会导致其功能失调及肝脏稳态失衡，促进肝纤维化发生发展。因此，LSEC靶向性递送NO供体有助于改善肝纤维化。然而，目前单一清道夫受体（SR）介导的药物递送系统难以实现LSEC特异性靶向，限制了靶向调控LSEC相关研究。预实验中，申请人发现LSEC特异性高表达NRP1受体，推测NRP1受体是协同靶向LSEC的理想靶标。在此基础上，本项目拟将具有SR-B1靶向功能的D4F多肽和具有NRP1靶向功能的RGE多肽共价融合，构建SR-B1/NRP1双靶向的新型安全的仿高密度脂蛋白（HDL）纳米载体，为靶向调控LSEC提供药物递送新载体；同时巧妙地运用HDL逆向运输胆固醇的特性，将胆固醇修饰的NO供体包裹在仿HDL纳米载体的疏水核心，改善LSEC功能失调及肝脏稳态失衡，为抗肝纤维化治疗提供新策略。

Liver sinusoidal endothelial cell (LSEC) is an important “gatekeeper” of liver immune homeostasis. Inhibition of nitric oxide (NO) synthesis can lead to LSEC dysfunction and liver homeostasis imbalance, and then promote the occurrence and development of liver fibrosis. Therefore, LSEC-targeted delivery of NO donor helps to improve liver fibrosis. However, at present, single scavenger receptor (SR)-mediated drug delivery system is difficult to achieve specific targeting of LSEC, which limits the research on targeted regulation of LSEC. In the preliminary experiments, the applicant found that LSEC specifically expressed high levels of NRP1 receptor, and speculated that NRP1 was an ideal target for synergistic targeting of LSEC. On the basis of this，the research project intends to construct a novel safe high-density lipoprotein (HDL) mimetic nanocarrier with SR-B1/NRP1 dual-targeting function by covalently fusing SR-B1-targeting D4F peptide and NRP1-targeting RGE peptide, thus providing a new carrier for LSEC-targeting drug delivery; By using the properties of HDL in the reverse transport of cholesterol skillfully, the cholesterol-modified NO donors are encapsulated in the hydrophobic core of HDL mimetic nanocarrier to regulate the dysfunction of LSEC and imbalance of liver homeostasis, thus providing a new strategy for the treatment of liver fibrosis.