Jin Yi, Tang Zhiyuan, Shang Shibeilei, Chen Yun, Han Guochen, Song Mingjie, Zhou Jianping, Zhang Huaqing, Ding Yang
State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing, 210009, China.
Department of Pharmacy, Affiliated Hospital of Nantong University, Nantong, 226000, China.
Adv Mater. 2023 Oct;35(40):e2302367. doi: 10.1002/adma.202302367. Epub 2023 Aug 16.
Mesenchymal stem cell (MSC) therapies experience steadfast clinical advances but are still hindered by inefficient site-specific migration. An adaptable MSC membrane fusogenicity technology is conceptualized for lipid raft-mediated targeting ligand embedding by using toolkits of discoidal high-density lipoprotein (HDL)-containing biomimicking 4F peptides. According to the pathological clues of brain diseases, the vascular cell adhesion molecule 1 specialized VBP peptide is fused with 4F to assemble 4F-VBP (HDL), which acts as a biobridge and transfers VBP onto the living cell membrane via lipid rafts for surface engineering of MSCs in suspension. When compared with the membrane-modifying strategies of PEGylated phospholipids, 4F-VBP (HDL) provides a 3.86 higher linkage efficiency to obtain MSCs , which can recognize and adhere to the inflammatory endothelium for efficient blood-brain barrier crossing and brain accumulation. In APPswe/PSEN1dE9 mice with Alzheimer's disease (AD), the transcriptomic analysis reveals that systemic administration of MSCs can activate pathways associated with neuronal activity and diminish neuroinflammation for rewiring AD brains. This customizable HDL-mediated membrane fusogenicity platform primes MSC inflammatory brain delivery, which can be expanded to other disease treatments by simply fusing 4F with relevant ligands for living cell engineering.
间充质干细胞（MSC）疗法在临床应用上取得了稳步进展，但仍受限于低效的位点特异性迁移。一种适应性强的MSC膜融合技术被提出，通过使用含盘状高密度脂蛋白（HDL）的仿生4F肽工具包，实现脂质筏介导的靶向配体嵌入。根据脑部疾病的病理线索，将血管细胞粘附分子1特异性VBP肽与4F融合，组装成4F-VBP（HDL），它作为生物桥，通过脂质筏将VBP转移到活细胞膜上，用于悬浮状态下MSC的表面工程改造。与聚乙二醇化磷脂的膜修饰策略相比，4F-VBP（HDL）获得MSC的连接效率高3.86倍，这些MSC能够识别并粘附于炎症内皮细胞，从而高效穿越血脑屏障并在脑内蓄积。在患有阿尔茨海默病（AD）的APPswe/PSEN1dE9小鼠中，转录组分析显示，全身给予MSC可激活与神经元活动相关的通路，并减轻神经炎症，以重塑AD大脑。这种可定制的HDL介导的膜融合平台为MSC向炎症脑的递送做好准备，通过简单地将4F与相关配体融合用于活细胞工程，该平台可扩展到其他疾病治疗。
