Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system

IF 37.2 1区材料科学 Q1 CHEMISTRY, PHYSICAL

Nature Materials Pub Date : 2025-02-17 DOI:10.1038/s41563-024-02114-5

Chang Wang, Yonger Xue, Tamara Markovic, Haoyuan Li, Siyu Wang, Yichen Zhong, Shi Du, Yuebao Zhang, Xucheng Hou, Yang Yu, Zhengwei Liu, Meng Tian, Diana D. Kang, Leiming Wang, Kaiyuan Guo, Dinglingge Cao, Jingyue Yan, Binbin Deng, David W. McComb, Ramon E. Parsons, Angelica M. Minier-Toribio, Leanne M. Holt, Jiayi Pan, Alice Hashemi, Brian H. Kopell, Alexander W. Charney, Eric J. Nestler, Paul C. Peng, Yizhou Dong

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Abstract

The systemic delivery of mRNA molecules to the central nervous system is challenging as they need to cross the blood–brain barrier (BBB) to reach into the brain. Here we design and synthesize 72 BBB-crossing lipids fabricated by conjugating BBB-crossing modules and amino lipids, and use them to assemble BBB-crossing lipid nanoparticles for mRNA delivery. Screening and structure optimization studies resulted in a lead formulation that has substantially higher mRNA delivery efficiency into the brain than those exhibited by FDA-approved lipid nanoparticles. Studies in distinct mouse models show that these BBB-crossing lipid nanoparticles can transfect neurons and astrocytes of the whole brain after intravenous injections, being well tolerated across several dosage regimens. Moreover, these nanoparticles can deliver mRNA to human brain ex vivo samples. Overall, these BBB-crossing lipid nanoparticles deliver mRNA to neurons and astrocytes in broad brain regions, thereby being a promising platform to treat a range of central nervous system diseases.

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通过血脑屏障脂质纳米颗粒将mRNA传递到中枢神经系统

mRNA分子向中枢神经系统的全身递送具有挑战性，因为它们需要穿过血脑屏障（BBB）才能进入大脑。本研究设计并合成了72种由血脑屏障穿越模块和氨基脂质偶联而成的血脑屏障穿越脂质，并利用它们组装血脑屏障穿越脂质纳米颗粒用于mRNA递送。筛选和结构优化研究结果表明，与fda批准的脂质纳米颗粒相比，这种先导制剂具有更高的mRNA传递到大脑的效率。在不同的小鼠模型中进行的研究表明，这些穿过血脑屏障的脂质纳米颗粒可以在静脉注射后转染整个大脑的神经元和星形胶质细胞，并且在多种剂量方案中都具有良好的耐受性。此外，这些纳米颗粒可以将mRNA传递到离体人脑样品中。总的来说，这些穿越血脑屏障的脂质纳米颗粒将mRNA传递到广泛的脑区域的神经元和星形胶质细胞，从而成为治疗一系列中枢神经系统疾病的有希望的平台。

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来源期刊

Nature Materials 工程技术-材料科学：综合

CiteScore

62.20

自引率

0.70%

发文量

221

审稿时长

3.2 months

期刊介绍： Nature Materials is a monthly multi-disciplinary journal aimed at bringing together cutting-edge research across the entire spectrum of materials science and engineering. It covers all applied and fundamental aspects of the synthesis/processing, structure/composition, properties, and performance of materials. The journal recognizes that materials research has an increasing impact on classical disciplines such as physics, chemistry, and biology. Additionally, Nature Materials provides a forum for the development of a common identity among materials scientists and encourages interdisciplinary collaboration. It takes an integrated and balanced approach to all areas of materials research, fostering the exchange of ideas between scientists involved in different disciplines. Nature Materials is an invaluable resource for scientists in academia and industry who are active in discovering and developing materials and materials-related concepts. It offers engaging and informative papers of exceptional significance and quality, with the aim of influencing the development of society in the future.