通过全身施用 GSH 响应性二氧化硅纳米胶囊克服基因治疗的血脑屏障,Advanced Materials

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通过全身施用 GSH 响应性二氧化硅纳米胶囊克服基因治疗的血脑屏障
Advanced Materials ( IF 27.4 ) Pub Date : 2022-11-29 , DOI: 10.1002/adma.202208018
Yuyuan Wang _{1,

2,

3} , Xiuxiu Wang _{1,

2,

3} , Ruosen Xie _{1,

2,

3} , Jacobus C Burger _{2,

3} , Yao Tong _{2,

3} , Shaoqin Gong _{1,

2,

3,

4,

5}

Affiliation

CRISPR 基因组编辑可以潜在地治疗许多遗传疾病的根本原因，包括中枢神经系统 (CNS) 疾病。然而，以脑为目标的治疗性基因组编辑的前景依赖于绕过血脑屏障 (BBB) 的生物制剂的有效递送，这是 CRISPR 疗法开发中的主要挑战。我们创建并筛选了一个谷胱甘肽 (GSH) 响应性二氧化硅纳米胶囊 (SNC) 库，用于通过全身给药进行脑靶向递送生物制剂。体内研究表明，在血糖控制下全身递送与葡萄糖和狂犬病病毒糖蛋白肽结合的 SNC 可以有效地绕过完整的 BBB，实现各种生物制剂的全脑递送，包括针对 Ai14 报告小鼠和野生型小鼠中不同基因的 CRISPR 基因组编辑器。特别是，在 Ai14 小鼠中，通过全身传递 Cre mRNA 进行高达 28% 的神经元编辑，高达 6.1% 的淀粉样前体蛋白（App ) 基因编辑（导致完整 APP 表达水平降低 19.1%），以及在野生型小鼠中高达 3.9% 的酪氨酸羟化酶 ( Th ) 基因编辑（导致 TH 表达水平降低 30.3%）观察到的。这种多功能的 SNC 纳米平台可能为治疗中枢神经系统疾病（包括阿尔茨海默氏症、帕金森氏症和亨廷顿舞蹈症）提供一种新的策略。

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

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.

更新日期：2022-11-29

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