The glymphatics system of the brain rapidly clears organic nanoparticles commonly used for brain drug delivery. To enhance drug or gene delivery to the brain, investigators have proposed the use of nanoparticulate delivery vectors to improve pharmacokinetics and pharmacodistribution. Once blood-brain barrier crossing is achieved, it has been assumed that nanoparticles would have a relatively prolonged residence time in the central nervous system, long enough for the payload to reach the target cells of interest. Indeed, earlier pharmacokinetic studies with inorganic nanoparticles, such as iron oxide, supported this assumption of prolonged brain residence times of nanoparticulate agents. Recently, Gu et al. studied the residence time in the brain of organic, biodegradable nanoparticles that are more typically used for drug delivery. They found that nanoparticles composed of either lipoproteins or polymers cleared fairly rapidly from the mouse brain following direct intraparenchymal injection, with a clearance half-life of only a few hours. Moreover, they found that this clearance was mediated, for the most part, by the glymphatic system—a recently described mechanism by which the brain's interstitial fluid clears into the lymphatic system of the body via paravascular channels—with the resident immune cells of the brain playing a pivotal role. From a drug delivery perspective, this implies that bioengineers must not assume that delivery of a nanoparticle past the blood-brain barrier will be sufficient and instead consider that the glymphatic system could clear the nanoparticle nearly as fast as it is being delivered. Additionally, this implies that nanoparticles may be uniquely suited for studying how the glymphatic system clears different types of materials from the brain, as well as the role of immune cells in this process. Furthermore, given that they are selectively cleared by immune cells into the glymphatic system, this suggests that nanoparticles could be uniquely suited to treating neuroinflammatory and neurodegenerative disorders. Certainly, although these data are compelling, future studies will need to verify that these results translate to larger animals that better predict the human situation. Additionally, they will need to be realized in realistic models of the diseases the nanoparticles are intended to treat. Overall, this study underlines the importance of explicitly verifying the pharmacokinetics and pharmacodistribution of drug delivery technologies.
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