Abstract：
A brain-targeting nanodelivery system has been a hot topic and has undergone rapid progression. However, due to various obstacles such as the intestinal epithelial barrier (IEB) and the blood-brain barrier (BBB), few nanocarriers can achieve brain-targeting through oral administration. Herein, an intelligent oral brain-targeting nanoparticle (FTY@Man NP) constructed from a PLGA-PEG skeleton loaded with fingolimod (FTY) and externally modified with mannose was designed in combination with a glucose control strategy for the multitarget treatment of Alzheimer\'s disease (AD). The hydrophilic and electronegative properties of the nanoparticle facilitated its facile penetration through the mucus barrier, while the mannose ligand conferred IEB targeting abilities to the nanoparticle. Subsequently, glycemic control allowed the mannose-integrated nanoparticle to hitchhike the glucose transporter 1 (GLUT1) circulation across the BBB. Finally, the released FTY modulated the polarity of microglia from pro-inflammatory M1 to anti-inflammatory M2 and normalized the activated astrocyte, enhancing the clearance of toxic protein Amyloid-β (Aβ) while alleviating oxidative stress and neuroinflammation. Notably, both in vitro and in vivo results have consistently demonstrated that the oral administration of FTY@Man NP could effectively traverse the multiple barriers, thereby exerting significant therapeutic effects. This breakthrough holds the promise of realizing a highly effective orally administered treatment for AD.
摘要：
脑靶向纳米递送系统一直是热门话题并且经历了快速发展。然而,由于各种障碍，如肠上皮屏障（IEB）和血脑屏障（BBB），很少有纳米载体可以通过口服实现脑靶向。在这里，设计了一种智能口服脑靶向纳米颗粒（FTY@ManNP），该纳米颗粒由PLGA-PEG骨架构建，负载芬戈莫德（FTY），并在外部用甘露糖修饰，并结合葡萄糖控制策略用于阿尔茨海默病（AD）的多目标治疗。纳米颗粒的亲水性和电负性特性促进了其通过粘液屏障的容易渗透，而甘露糖配体赋予纳米粒子IEB靶向能力。随后，血糖控制允许甘露糖整合的纳米颗粒搭便车通过BBB的葡萄糖转运蛋白1（GLUT1）循环。最后,释放的FTY将小胶质细胞的极性从促炎M1调节为抗炎M2，并使活化的星形胶质细胞正常化，增强毒性蛋白淀粉样β（Aβ）的清除，同时减轻氧化应激和神经炎症。值得注意的是,体外和体内结果一致表明，口服FTY@ManNP可以有效地穿越多个屏障，从而发挥显著的治疗效果。这一突破有望实现AD的高效口服治疗。
