Brain interstitial system (ISS) is a nanoscale network of continuously connected tubes and sheets surrounding each neural cell in the central nervous system. ISS usually accounts for ∼20% of the brain volume, far more than the cerebral blood vessels, which account for 3%. The neuronal function, signaling pathways, and drug delivery are all closely related to the microenvironment provided by ISS. The objective of this paper is to give the readers a clear outline of detection, anatomy, function, and applications of ISS. This review describes the techniques propelling the exploration for ISS in chronological order, physiological function and pathological dysfunction of ISS, and strategies for drug delivery based on ISS. Biophysical features are the focus of ISS research, in which the diffusion characteristics have dominated. The various techniques that explore ISS take advantage of this feature. ISS provides an essential microenvironment for the health of cells and brain homeostasis, which plays an important functional role in brain health and disease. Direct intracranial administration allows the diffusion of drugs directly through ISS to successfully bypass the blood–brain barrier that prevents most drugs from reaching the brain. With the deepening of understanding of the brain ISS, the new research model that takes into account brain cells, cerebral vessels, and ISS will provide a new perspective and direction for understanding, utilizing, and protecting the brain.

中文翻译：

---

探索大脑间质系统：药物输送的最后一英里

脑间质系统 (ISS) 是一个纳米级网络，由围绕中枢神经系统中每个神经细胞的连续连接的管和片组成。ISS通常占大脑体积的~20%，远远超过占3%的脑血管。神经元功能、信号通路和药物输送都与ISS提供的微环境密切相关。本文旨在让读者对国际空间站的检测、解剖、功能和应用有一个清晰的概述。本综述按时间顺序描述了推动 ISS 探索的技术、ISS 的生理功能和病理功能障碍，以及基于 ISS 的药物递送策略。生物物理特征是国际空间站研究的重点，其中扩散特征占主导地位。探索 ISS 的各种技术都利用了这一特性。ISS 为细胞健康和大脑稳态提供了一个必不可少的微环境，它在大脑健康和疾病中起着重要的功能作用。直接颅内给药允许药物直接通过 ISS 扩散，成功绕过阻止大多数药物到达大脑的血脑屏障。随着人们对大脑ISS认识的不断深入，这种将脑细胞、脑血管和ISS纳入考虑的新研究模型将为理解、利用和保护大脑提供新的视角和方向。它在大脑健康和疾病中起着重要的功能作用。直接颅内给药允许药物直接通过 ISS 扩散，成功绕过阻止大多数药物到达大脑的血脑屏障。随着人们对大脑ISS认识的不断深入，这种将脑细胞、脑血管和ISS纳入考虑的新研究模型将为理解、利用和保护大脑提供新的视角和方向。它在大脑健康和疾病中起着重要的功能作用。直接颅内给药允许药物直接通过 ISS 扩散，成功绕过阻止大多数药物到达大脑的血脑屏障。随着人们对大脑ISS认识的不断深入，这种将脑细胞、脑血管和ISS纳入考虑的新研究模型将为理解、利用和保护大脑提供新的视角和方向。