血脑屏障（BBB）在决定治疗脑部疾病的全身性治疗的有效性方面起着关键作用。多年来，已开发出并成功进入临床试验阶段的几种创新的BBB开放和药物输送方法,包括聚焦超声（FUS）与微泡循环、曼尼托（mannitol）促进的抗肿瘤药物输送、抗体药物偶联物介导的穿透性转运（RMT）、以及用于基因治疗的病毒载体。我们对这些方法在管理脑肿瘤和阿尔茨海默病（AD）这两种重大破坏性脑疾病中最近的临床应用进行了全面的回顾。此外，在疾病状态下，BBB的时空分子异质性强调了利用新兴的时空系统生物学方法来解开BBB内的干预新目标和定制增强脑部药物输送的策略的重要性。搜索策略和选择标准：通过在clinicaltrials.gov、MEDLINE、Current Contents、PubMed以及相关文章的参考文献中使用“blood-brain barrier”、“CNS drug delivery”、“BBB modulation”、“clinical trials”、“systems biology”、“primary or metastatic brain tumors”、“Alzheimer's disease”等搜索词来确定本综述的数据。仅当摘要和会议报告与先前出版的作品直接相关时，才包括在内。仅包括1980年至2023年之间发表的英文文章。版权所有 © 2023 The Authors. Elsevier Masson SAS 发表。保留所有权利。

The blood-brain barrier (BBB) plays a critical role in determining the effectiveness of systemic treatments for brain diseases. Over the years, several innovative approaches in BBB opening and drug delivery have been developed and progressed into clinical testing phases, including focused ultrasound (FUS) with circulating microbubbles, mannitol-facilitated delivery of anti-neoplastic drugs, receptor-mediated transcytosis (RMT) by antibody-drug conjugates (ADCs), and viral vectors for gene therapy. We provided a comprehensive review of the most recent clinical applications of these approaches in managing brain tumors and Alzheimer's disease (AD), two major devastating brain diseases. Moreover, the spatial-temporal molecular heterogeneity of the BBB under disease states emphasized the importance of utilizing emerging spatial systems biology approaches to unravel novel targets for intervention within BBB and tailor strategies for enhancing drug delivery to the brain. SEARCH STRATEGY AND SELECTION CRITERIA: Data for this Review were identified by searches of clinicaltrials.gov, MEDLINE, Current Contents, PubMed, and references from relevant articles using the search terms "blood-brain barrier", "CNS drug delivery", "BBB modulation", "clinical trials", "systems biology", "primary or metastatic brain tumors", "Alzheimer's disease". Abstracts and reports from meetings were included only when they related directly to previously published work. Only articles published in English between 1980 and 2023 were included.Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.