Development of novel therapies for central nervous system (CNS) disorders has experienced a high failure rate in clinical trials owing to unsatisfactory efficacy and adverse effects. One of the major reasons for limited therapeutic efficacy is the poor penetration of drugs across the blood–brain barrier. Despite the development of multiple drug delivery platforms, the overall drug accumulation in the brain remains sub-optimal. Another critical but overlooked factor is achieving precision delivery to a specific region and cell type in the brain. This specificity is crucial because most neurological disorders exhibit region-specific vulnerabilities. Multiple trials have failed owing to adverse CNS effects induced by nonspecific drug targeting. In this Review, we highlight the key regions and cell types that should be targeted in different CNS diseases. We discuss how physiological barriers and disease-mediated changes in the blood–brain barrier and the overall brain can impact the precision delivery of therapeutics via the systemic route. We then perform a systematic analysis of the current state-of-the-art approaches developed to overcome these barriers and achieve precision targeting at different levels. Finally, we discuss potential approaches to accelerate the development of precision delivery systems and outline the challenges and future research directions.

由于疗效不理想和不良反应，中枢神经系统（CNS）疾病的新疗法的开发在临床试验中经历了很高的失败率。治疗效果有限的主要原因之一是药物穿过血脑屏障的渗透性差。尽管开发了多种药物递送平台，但大脑中的总体药物积累仍然不理想。另一个关键但被忽视的因素是实现对大脑中特定区域和细胞类型的精确递送。这种特异性至关重要，因为大多数神经系统疾病都表现出区域特异性的脆弱性。由于非特异性药物靶向引起的中枢神经系统不良反应，多项试验都失败了。在这篇综述中，我们重点介绍了不同中枢神经系统疾病应针对的关键区域和细胞类型。我们讨论血脑屏障和整个大脑的生理障碍和疾病介导的变化如何影响通过全身途径的治疗的精确递送。然后，我们对当前为克服这些障碍并实现不同级别的精确定位而开发的最先进方法进行系统分析。最后，我们讨论了加速精准输送系统开发的潜在方法，并概述了挑战和未来的研究方向。