Glymphatic System and Subsidiary Pathways Drive Nanoparticles Away from the Brain

Although drug delivery systems (DDS) are efficient in brain delivery, they face failure in clinical settings due to their potential toxicity to the central nervous system. Little is known about where the DDS will go after brain delivery, and no specific elimination route that shares a passage with DDS has been verified. Hence, identifying harmless DDS for brain delivery and determining their fate there would strongly contribute to their clinical translation. In this study, we investigated nonreactive gold nanoclusters, which can deliver into the brain, to determine the elimination route of DDS. Subsequently, nanoclusters in the brain were systemically tracked and were found to be critically drained by the glymphatic system from the blood vessel basement membrane to periphery circulations (77.8 ± 23.2% and 43.7 ± 23.4% contribution). Furthermore, the nanoclusters could be actively transported across the blood-brain barrier (BBB) by exosomes (30.5 ± 27.3% and 29.2 ± 7.1% contribution). In addition, microglia promoted glymphatic drainage and passage across the BBB. The simultaneous work of the glymphatic system, BBB, and microglia revealed the fate of gold nanoclusters for brain delivery and provided a basis for further brain-delivery DDS.