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 and Huile Gao ()
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Qiguang Wang: Sichuan University
Xue Xia: Sichuan University
Huan Zhang: Sichuan University
Yue Li: Sichuan University
Lei Zhu: Sichuan University
Yulong Shi: Sichuan University
Yuzhao Tang: Sichuan University
Jian Cheng: Sichuan University
Xuhui Hui: Sichuan University
Huile Gao: Sichuan University

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-61543-1

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