Xiaolei Wu, Bin Du, Qian Chen, Ruyi Hang, Ce Cui, Mengxia Li
The central nervous system has long been considered an immune-privileged organ, but discoveries about meningeal lymphatics, meningeal immune cells, cerebrospinal fluid (CSF)-interstitial fluid (ISF) exchange, and aquaporin-4 (AQP4)-associated glymphatic-like transport are reshaping our understanding of waste clearance and immune surveillance in the brain. However, there are obvious breaks in the current model system. Animal models possess complete circulatory and meningeal structures, but are limited by species differences, imaging depth, operability, and high throughput. Traditional two-dimensional (2D) culture and transwell models lack 3D brain parenchymal structure, low-speed fluid dynamics, and the meningeal immune microenvironment. This paper proposes the concept of “brain parenchyma-lymphoid-meningeal immune assembly chip”, which integrates brain organoids containing neurons, astrocytes and microglia, CSF-like fluid derived from choroid plexus organoids, microfluidic lymphatic channels, and meningeal immune modules containing meningeal lymphatic endothelium, meningeal fibroblasts, macrophages, and dendritic cells. Currently, the various component technologies required for this platform are still at different stages of experimental maturity and have not yet been integrated into a single system. This review discusses existing issues such as the cellular composition of the brain parenchyma module, the engineering simulation of glymphatic dynamics, the reconstruction of the meningeal lymphatic and immune interface, disease applications, and validation standards. It also outlines a phased development roadmap to build a platform capable of tracking the continuous process of “pathological product generation-fluid clearance-meningeal immune sensing-inflammatory feedback” under simulated human brain conditions, providing new tools for mechanism analysis and drug screening in neurodegenerative diseases, brain injury, and neuro-immunological diseases.