Current strategies to direct therapy-loaded nanoparticles to the brain rely on functionalizing nanoparticles with ligands which bind target proteins associated with the blood–brain barrier (BBB). However, such strategies have significant brain-specificity limitations, as target proteins are not exclusively expressed at the brain microvasculature. Therefore, novel strategies which exploit alternative characteristics of the BBB are required to overcome nonspecific nanoparticle targeting to the periphery, thereby increasing drug efficacy and reducing detrimental peripheral side effects. Here, we present a simple, yet counterintuitive, brain-targeting strategy which exploits the higher impermeability of the BBB to selectively label the brain endothelium. This is achieved by harnessing the lower endocytic rate of brain endothelial cells (a key feature of the high BBB impermeability) to promote selective retention of free, unconjugated protein-binding ligands on the surface of brain endothelial cells compared to peripheral endothelial cells. Nanoparticles capable of efficiently binding to the displayed ligands (i.e., labeled endothelium) are consequently targeted specifically to the brain microvasculature with minimal “off-target” accumulation in peripheral organs. This approach therefore revolutionizes brain-targeting strategies by implementing a two-step targeting method which exploits the physiology of the BBB to generate the required brain specificity for nanoparticle delivery, paving the way to overcome targeting limitations and achieve clinical translation of neurological therapies. In addition, this work demonstrates that protein targets for brain delivery may be identified based not on differential tissue expression, but on differential endocytic rates between the brain and periphery.

目前，将载有治疗剂的纳米颗粒引导到大脑的策略依赖于用结合与血脑屏障（BBB）相关的靶蛋白的配体对纳米颗粒进行功能化。然而，由于靶蛋白并非仅在脑微脉管系统中表达，因此这种策略具有明显的脑特异性限制。因此，需要新的策略来利用BBB的替代特征，以克服非特异性纳米粒子靶向外周的作用，从而提高药物疗效并减少有害的外周副作用。在这里，我们提出了一种简单而又违反直觉的大脑靶向策略，该策略利用BBB的较高不渗透性来选择性标记大脑内皮。这是通过利用较低的脑血管内皮细胞内吞率（高血脑屏障通透性的关键特征）来实现的，与周围内皮细胞相比，可促进游离，未结合的蛋白结合配体选择性保留在脑内皮细胞表面。因此，能够有效结合展示的配体（即标记的内皮）的纳米颗粒被特异性地靶向大脑微脉管系统，而在外围器官中的“脱靶”积累最少。因此，该方法通过实施两步靶向方法彻底改变了大脑靶向策略，该方法利用BBB的生理学来生成纳米粒子递送所需的大脑特异性，为克服靶向限制和实现神经疗法的临床翻译铺平了道路。