Targeting modulation of the choroid plexus blood-CSF barrier and CSF hypersecretion via lipid nanoparticle-mediated co-delivery of siRNA and resveratrol
Qiguang Wang, Xue Xia, Huan Zhang, Yue Li, Lei Zhu, Yulong Shi, Yuzhao Tang, Jian Cheng, Xuhui Hui, Huile Gao
Abstract
Hydrocephalus is one of the most common neurological disorders, but pharmacotherapy options are currently lacking due to the complex pathogenesis. The blood-CSF barrier (BCSFB), consisting of choroid plexus (ChP) epithelial cells, is a crucial gate for the entry of peripheral immune cells and its dysfunction emerges as an important contributor to hydrocephalus pathology. Meanwhile, SPAK-mediated CSF hypersecretion in ChP epithelial cells plays an important role in hydrocephalus. Here, we fabricated a transferrin receptor-targeted nano-drug (siR/RSV@TNP) that can intelligently navigate to the blood-CSF barrier and prepared for combined delivery of resveratrol (RSV) and SPAK siRNA (siSPAK) for synergetic hydrocephalus therapy. As expected, siR/RSV@TNP fulfilled its function of knocking down SPAK expression, relieving inflammation and oxidative stress, retrieving blood-CSF barrier integrity, and ultimately preventing ventriculomegaly and hydrocephalus in male mice. Here, we demonstrate that targeting the choroid plexus blood-CSF barrier and cerebrospinal fluid hypersecretion offers a promising approach for alleviating hydrocephalus. Hydrocephalus, a disorder characterized by cerebrospinal fluid (CSF) overproduction and impaired blood-CSF barrier function, lacks effective non-invasive treatments. Here, authors show that a multi-functional nanomedicine (siR/RSV@TNP) combining anti-inflammatory resveratrol and SPAK siRNA restores blood-CSF barrier integrity, reduces CSF overproduction, and prevents hydrocephalus in mice, offering a promising therapeutic strategy.