Microglial extracellular vesicles define the brain clearance pattern of nanomaterials

Nanoparticles (NPs) represent an important advance for delivering diagnostic and therapeutic agents across the blood-brain barrier. Systematic elucidation of the intracerebral destiny of nanomaterials is critical for their safety and therapeutic applicability. However, the NPs clearance from the brain and underlying mechanisms are still largely unknown. In this study, we found that microglial extracellular vesicles (EVs) play a crucial role in brain clearance of inorganic and organic NPs. The inorganic NPs (quantum dots, QD and gold NPs, AuNP), unlike organic reconstituted high density lipoprotein (rHDL) and poly(ethylene glycol)-b-poly(lactic acid) (PEG-PLA) NPs, perturbed microglial EVs biogenesis through the inhibition of ERK1/2 signaling, aggravated NPs accumulation in microglia and hindered their elimination via the paravascular route. Furthermore, the induced release of microglial EVs by an ERK1/2 activator pamoic acid, increased paravascular glymphatic pathway-mediated brain clearance for both QD and AuNP by 5.46 and 28.50-fold, respectively. These findings highlight the modulatory role of microglial EVs on distinct patterns of the inorganic and organic NPs clearance from the brain and provide a proof of concept strategy for modulating the intracerebral fate of engineered NPs.