The blood-brain barrier, a key bridge to treat neurodegenerative diseases.

As a highly selective and semi-permeable barrier that separates the circulating blood from the brain and central nervous system (CNS), the blood-brain barrier (BBB) plays a critical role in the onset and treatment of neurodegenerative diseases (NDs). To delay or reverse the NDs progression, the dysfunction of BBB should be improved to protect the brain from harmful substances. Simultaneously, a highly efficient drug delivery across the BBB is indispensable. Here, we summarized several methods to improve BBB dysfunction in NDs, including knocking out risk geneAPOE4, regulating circadian rhythms, restoring the gut microenvironment, and activating the Wnt/β-catenin signaling pathway. Then we discussed the advances in BBB penetration techniques, such as transient BBB opening, carrier-mediated drug delivery, and nasal administration, which facilitates drug delivery across the BBB. Furthermore, various in vivo and in vitro BBB models and research methods related to NDs are reviewed. Based on the current research progress, the treatment of NDs in the long term should prioritize the integrity of the BBB. However, a treatment approach that combines precise control of transient BBB permeability and non-invasive targeted BBB drug delivery holds profound significance in improving treatment effectiveness, safety, and clinical feasibility during drug therapy. This review involves the cross application of biology, materials science, imaging, engineering and other disciplines in the field of BBB, aiming to provide multi-dimensional research directions and clinical ideas for the treating NDs.