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. 2024 Mar;19(3):376-386.
doi: 10.1038/s41565-023-01551-8. Epub 2023 Dec 29.

Intracerebral fate of organic and inorganic nanoparticles is dependent on microglial extracellular vesicle function

Jinchao Gao  1 , Qingxiang Song  1 , Xiao Gu  1 , Gan Jiang  1 , Jialin Huang  1 , Yuyun Tang  1 , Renhe Yu  1 , Antian Wang  1 , Yukun Huang  1 , Gang Zheng  2 , Hongzhuan Chen  3 , Xiaoling Gao  4
Affiliations

Intracerebral fate of organic and inorganic nanoparticles is dependent on microglial extracellular vesicle function

Jinchao Gao et al. Nat Nanotechnol. 2024 Mar.

Abstract

Nanoparticles (NPs) represent an important advance for delivering diagnostic and therapeutic agents across the blood-brain barrier. However, NP clearance is critical for safety and therapeutic applicability. Here we report on a study of the clearance of model organic and inorganic NPs from the brain. We find that microglial extracellular vesicles (EVs) play a crucial role in the clearance of inorganic and organic NPs from the brain. Inorganic NPs, unlike organic NPs, perturb the biogenesis of microglial EVs through the inhibition of ERK1/2 signalling. This increases the accumulation of inorganic NPs in microglia, hindering their elimination via the paravascular route. We also demonstrate that stimulating the release of microglial EVs by an ERK1/2 activator increased the paravascular glymphatic pathway-mediated brain clearance of inorganic NPs. These findings highlight the modulatory role of microglial EVs on the distinct patterns of the clearance of organic and inorganic NPs from the brain and provide a strategy for modulating the intracerebral fate of NPs.

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