Special interstitial route can transport nanoparticles to the brain bypassing the blood-brain barrier

Nowadays, nanoparticles (NPs) are considered to be ideal tools for bioimaging and drug delivery. Although increasing research has focused on NP biodistribution, transportation in the interstitial architecture has been neglected. The entire body is connected by the interstitial architecture, which can provide a long-range and direct pathway for NP biodistribution in a nonvascular system. In this study, we report that 10-nm gold NPs injected directly into the interstitial architecture of the tarsal tunnel of rats (intervaginal space injection (ISI)) were delivered to the brain without crossing the blood-brain barrier. Furthermore, NaGdF₄ nanoparticles were used to explore the transportation route by magnetic resonance imaging. The results demonstrated that, after ISI, the NaGdF₄ nanoparticles were transported through the perivascular interstitial space of the carotid arteries and brain vessels to the brain. This is a special nonvascular transportation route like a stream based on the interstitial architecture that provides an alternative pathway for NP biodistribution.