Targeting modulation of the choroid plexus blood-CSF barrier and CSF hypersecretion via lipid nanoparticle-mediated co-delivery of siRNA and resveratrol

作者：Qiguang Wang, Xue Xia, Huan Zhang, Yue Li, Lei Zhu, Yulong Shi, Yuzhao Tang, Jian Cheng, Xuhui Hui, Huile Gao · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-61543-1 · 被引用次数：21 · 研究领域：Nanoplatforms for cancer theranostics、RNA Interference and Gene Delivery、Nanoparticle-Based Drug Delivery

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 overproduct...