Nanocarriers (NCs) are promising tools to improve drug delivery across the blood–brain barrier (BBB) for more effective treatment of brain disorders, although there is a scarcity of clinical translation of brain-directed NCs. In order to drive the development of brain-oriented NCs toward clinical success, it is essential to understand the prerequisites for nanodelivery to be successful in brain treatment. In this Perspective, we present how pharmacokinetic/pharmacodynamic (PK/PD), formulation and nanotoxicity factors impact the therapeutic success of brain-specific nanodelivery. Properties including high loading efficiency, slow in vivo drug release, long systemic circulation, an increase in unbound brain-to-plasma concentration/exposure ratio (K_p,uu,brain), high drug potency, and minimal nanotoxicity are prerequisites that should preferably be combined to maximize the therapeutic potential of a brain-targeted NC. The PK of brain-directed NCs needs to be evaluated in a more therapeutically relevant manner, focusing on the released, unbound drug. It is more crucial to increase the K_p,uu,brain than to improve the ability of the NC to cross the BBB in its intact form. Brain-targeted NCs, which are mostly developed for treating brain tumors, including metastases, should aim to enhance drug delivery not just to tumor regions with disrupted BBB, but equally important to regions with intact BBB where the drugs themselves have problems reaching. This article provides critical insights into how a brain-targeted nanoformulation needs to be designed and optimized to achieve therapeutic success in the brain.

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对大脑纳米递送的看法：成功大脑治疗的先决条件

纳米载体 (NCs) 是改善药物跨血脑屏障 (BBB) 递送的有前途的工具，以更有效地治疗脑部疾病，尽管大脑导向的 NCs 缺乏临床转化。为了推动面向大脑的 NC 向临床成功发展，了解纳米递送在大脑治疗中取得成功的先决条件至关重要。在这个视角中，我们介绍了药代动力学/药效学 (PK/PD)、配方和纳米毒性因素如何影响大脑特异性纳米递送的治疗成功。特性包括高负载效率、体内药物释放缓慢、体循环长、未结合的脑与血浆浓度/暴露比（K _p,uu,brain)、高药物效力和最小的纳米毒性是最好结合起来以最大化脑靶向 N​​C 的治疗潜力的先决条件。需要以更具治疗相关性的方式评估大脑导向 NC 的 PK，重点是释放的未结合药物。增加K _p,uu,brain更为关键而不是提高 NC 以其完整形式穿过 BBB 的能力。脑靶向 N​​Cs 主要用于治疗脑肿瘤，包括转移瘤，其目标不仅是增强对 BBB 破坏的肿瘤区域的药物递送，而且对于药物本身难以到达的完整 BBB 区域也同样重要。本文提供了有关如何设计和优化大脑靶向纳米制剂以在大脑中取得治疗成功的重要见解。