Overcoming the Blood-Brain Barrier for Gene Therapy via Systemic Administration of GSH-Responsive Silica Nanocapsules.

CRISPR genome editing has demonstrated great potential to treat the root causes of many genetic diseases, including central nervous system (CNS) disorders. However, the promise of brain-targeted therapeutic genome editing relies on the efficient delivery of biologics bypassing the blood-brain barrier (BBB), which represents a substantial challenge in the development of CRISPR therapeutics. In this study, we created a library of GSH-responsive silica nanocapsules (SNCs) and screened them for brain targeting via systemic delivery of nucleic acids and CRISPR genome editors. In vivo studies demonstrated that systemically delivered SNCs conjugated with glucose and RVG peptide under glycemic control can efficiently bypass the intact BBB, enabling brain-wide delivery of various biologics (mRNA, Cas9 mRNA/sgRNA, and Cas9/sgRNA ribonucleoprotein) targeting both exogenous genes (i.e., Ai14 stop cassette) and disease-relevant endogenous genes (i.e., App and Th genes) in Ai14 reporter mice and wild-type mice, respectively. In particular, we observed up to 28% neuron editing via systemic delivery of Cre mRNA in Ai14 mice, up to 6.1% amyloid precursor protein (App) gene editing (resulting in 19.1% reduction in the expression level of intact APP), and up to 3.9% tyrosine hydroxylase (Th) gene editing (resulting in 30.3% reduction in the expression level of TH) in wild-type mice. This versatile SNC nanoplatform may offer a novel strategy for the treatment of CNS disorders including Alzheimer's, Parkinson's, and Huntington's disease. This article is protected by copyright. All rights reserved.