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

Abstract CRISPR genome editing can potentially 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 major challenge in the development of CRISPR therapeutics. We created and screened a library of glutathione (GSH)‐responsive silica nanocapsules (SNCs) for brain targeted delivery of biologics via systemic administration. In vivo studies demonstrate that systemically delivered SNCs conjugated with glucose and rabies virus glycoprotein peptide under glycemic control can efficiently bypass the intact BBB, enabling brain‐wide delivery of various biologics including CRISPR genome editors targeting different genes in both Ai14 reporter mice and wild‐type mice. In particular, 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 are observed. This versatile SNC nanoplatform may offer a novel strategy for the treatment of CNS disorders including Alzheimer's, Parkinson's, and Huntington's disease.