Intervaginal space injection (ISI) is a novel mode of administration investigated over the last decade. After injecting nanoparticles into the intervaginal space, they can be transported along low flow resistance channels into the interstitial space. This transport has a certain delivery direction, and site-specific injection can work on specific organs or tissues. In this study, the thorax, a new ISI site in the interstitial surrounding the internal thoracic artery named the thoracic interstitial injection (tISI) was investigated. To prove the targeting ability of the tISI, two sizes of gold nanoparticles (AuNPs) (47 and 87 nm) were administered to mice. After 1 h, the biodistribution of AuNPs in the tissues was measured via single particle inductively coupled plasma mass spectrometry (spICP-MS). The results showed that the concentration of AuNPs in the aorta after tISI injection was significantly higher than that after intravenous injection. Moreover, fewer nanoparticles with larger particle sizes were observed to have entered the blood and were better targeted to the aorta. Thereafter, tanshinone IIa sodium sulfonate liposomes were administered for the treatment of aortic atherosclerosis. The proportion of aortic plaques in atherosclerotic Apoe-/- mice administered via tISI was significantly lower than that in other model animals (P < 0.001). Furthermore, the proteoglycan content and CD68-positive cell count in the plaques were significantly reduced. The vascular elastic fibers at the plaque site were thickened, and fractures were reduced. tISI was, therefore, determined to be an effective strategy for the treatment of atherosclerotic aortic plaques.

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.