Glymphatic System and Subsidiary Pathways Drive Nanoparticles Away from the Brain

Area of Science:

• Nanomedicine
• Neuroscience
• Biotechnology

Background:

• Drug delivery systems (DDS) face clinical translation challenges due to potential central nervous system toxicity.
• The elimination routes and fate of DDS within the brain remain largely uncharacterized.
• Identifying safe DDS and understanding their brain clearance is crucial for therapeutic advancements.

Purpose of the Study:

• To investigate the elimination pathways of nonreactive gold nanoclusters (AuNCs) after brain delivery.
• To determine the contribution of the glymphatic system and blood-brain barrier (BBB) transport to AuNC clearance.
• To elucidate the role of microglia in the brain disposition of DDS.

Main Methods:

• Systemic tracking of gold nanoclusters (AuNCs) within the brain.
• Quantification of AuNC drainage via the glymphatic system.
• Assessment of AuNC transport across the blood-brain barrier mediated by exosomes.
• Evaluation of microglia's influence on glymphatic drainage and BBB passage.

Main Results:

• Gold nanoclusters were significantly drained by the glymphatic system (77.8% ± 23.2%) and cleared via peripheral circulation (43.7% ± 23.4%).
• Active transport across the blood-brain barrier by exosomes contributed to AuNC disposition (30.5% ± 27.3% and 29.2% ± 7.1%).
• Microglia were observed to enhance both glymphatic drainage and exosome-mediated BBB passage.

Conclusions:

• The glymphatic system and exosome-mediated BBB transport are key pathways for gold nanocluster elimination from the brain.
• Microglia play a supportive role in facilitating DDS clearance from the central nervous system.
• Understanding these clearance mechanisms provides a foundation for developing safer and more effective brain-targeted DDS.