A combination of systemic mannitol and mannitol modified polyester nanoparticles for caveolae-mediated gene delivery to the brain.

IF 6.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Molecular Therapy. Nucleic Acids Pub Date : 2025-02-06 eCollection Date: 2025-03-11 DOI:10.1016/j.omtn.2025.102480

Betsy Reshma Gilbert, Chirag Miglani, Arundhati Karmakar, Muneesh Pal, Vysakh C Chandran, Sarika Gupta, Asish Pal, Munia Ganguli

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引用次数: 0

Abstract

Overcoming the blood-brain barrier (BBB) remains a significant challenge for nucleic acid delivery to the brain. We have explored a combination of mannitol-modified poly (β-amino ester) (PBAE) nanoparticles and systemic mannitol injection for crossing the BBB. We incorporated mannitol in the PBAE polymer for caveolae targeting and selected monomers that may help avoid delivery to the liver. We also induced caveolae at the BBB through systemic mannitol injection in order to create an opportunity for the caveolae-targeting nanoparticles (M30 D90) containing plasmid DNA to cross the BBB. When a clinically relevant dose was administered intravenously in this caveolae induction model, M30 D90 demonstrated significant transgene expression of a reporter plasmid in the brain, with selective uptake by neuronal cells and minimal liver accumulation. We demonstrate that caveolae modulation using systemic mannitol administration and caveolae targeting using designed nanoparticles are necessary for efficient delivery to the brain. This delivery platform offers a simple, scalable, and controlled delivery solution and holds promise for treating brain diseases with functional targets.

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系统甘露醇和甘露醇改性聚酯纳米颗粒的组合，用于小泡介导的基因传递到大脑。

克服血脑屏障（BBB）仍然是核酸输送到大脑的一个重大挑战。我们已经探索了甘露醇修饰的聚（β-氨基酯）（PBAE）纳米颗粒和全身甘露醇注射剂的组合，以穿过血脑屏障。我们将甘露醇加入到PBAE聚合物中，用于小泡靶向和选择可能有助于避免递送到肝脏的单体。我们还通过全身注射甘露醇在血脑屏障处诱导小泡，为含有质粒DNA的靶向小泡纳米颗粒（M30 D90）穿过血脑屏障创造机会。当在这个小窝诱导模型中静脉给予临床相关剂量时，M30 D90在大脑中表现出显著的转基因报告质粒表达，被神经元细胞选择性摄取，肝脏积累最少。我们证明，使用系统甘露醇给药和使用设计的纳米颗粒靶向小泡是有效递送到大脑的必要条件。该输送平台提供了一种简单、可扩展、可控的输送解决方案，有望通过功能靶点治疗脑部疾病。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Therapy. Nucleic Acids MEDICINE, RESEARCH & EXPERIMENTAL-

CiteScore

15.40

自引率

1.10%

发文量

336

审稿时长

20 weeks

期刊介绍： Molecular Therapy Nucleic Acids is an international, open-access journal that publishes high-quality research in nucleic-acid-based therapeutics to treat and correct genetic and acquired diseases. It is the official journal of the American Society of Gene & Cell Therapy and is built upon the success of Molecular Therapy. The journal focuses on gene- and oligonucleotide-based therapies and publishes peer-reviewed research, reviews, and commentaries. Its impact factor for 2022 is 8.8. The subject areas covered include the development of therapeutics based on nucleic acids and their derivatives, vector development for RNA-based therapeutics delivery, utilization of gene-modifying agents like Zn finger nucleases and triplex-forming oligonucleotides, pre-clinical target validation, safety and efficacy studies, and clinical trials.