The cervical and meningeal lymphatic network as a pathway for retrograde nanoparticle transport to the brain

The meningeal lymphatic vessels have been described as a pathway that transports cerebrospinal fluid and interstitial fluid in a unidirectional manner towards the deep cervical lymph nodes. However, these vessels exhibit anatomical and molecular characteristics typical of initial lymphatic vessels, with the absence of surrounding smooth muscle and few or absent valves. Given its structure, this network could theoretically allow for bidirectional motion. Nevertheless, it has not been assessed as a potential route for nanoparticles to travel from peripheral tissues to the brain. Here we show that extracellular vesicles derived from the B16F10 melanoma cell line, along with superparamagnetic iron oxide nanoparticles, gold nanorods, and Chinese ink nanoparticles can reach the meningeal lymphatic vessels and the brain of C57BL/6 mice after administration within deep cervical lymph nodes in vivo, exclusively through lymphatic structures. Since the functional anatomy of dural lymphatics has been found to be conserved between mice and humans, we expect that our results will encourage further research into the retrograde motion of nanoparticles towards the brain for pharmacological purposes in nanomedicine, as well as to better understand the fluid dynamics in different physiological or neuropathological conditions.