二甲胺基合成类脂纳米颗粒选择性mRNA递送至脾脏抗原呈递细胞

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release Pub Date : 2025-04-13 DOI:10.1016/j.jconrel.2025.113737

Xue Liang , Chenchen Zhang , Qimeng Yin , Yuerong Bai , Jiahao Li , Min Qiu

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引用次数: 0

摘要

靶向全身性肝外组织mRNA递送仍然是一个艰巨的挑战，特别是在脂质纳米颗粒上缺乏靶向配体的情况下。在这项研究中，我们引入了一系列基于二甲胺的可电离脂质（DMA-Lipidoids），用于选择性地将mRNA递送到脾脏。利用组合方法，我们将4个含dma的胺头与12个新设计的超支化尾配对，合成了48个化学性质不同的脂质。值得注意的是，尾部为H228、H226x、H246x和H446x的脂质具有卓越的脾脏靶向效率。为了完善脂质设计，我们构建并筛选了含有DMA类似物的36个脂质二级文库。通过这两轮筛选过程，我们确定了高效和脾脏选择性的脂质。主要候选药物DMA4-H228实现了卵白蛋白mRNA向抗原呈递细胞（APC）的精确递送，驱动干扰素-α (IFN α)的产生和APC的激活。这种强大的免疫反应有效地抑制了肿瘤的生长。总的来说，这些创新的dma -脂质具有很强的脾脏靶向能力，为mRNA疫苗的开发提供了一个变革性的平台。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Dimethylamino-based synthetic lipidoid nanoparticles for selective mRNA delivery to splenic antigen-presenting cells

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Dimethylamino-based synthetic lipidoid nanoparticles for selective mRNA delivery to splenic antigen-presenting cells

Targeted systemic mRNA delivery to extrahepatic tissues remains a formidable challenge, especially in the absence of targeting ligands on lipid nanoparticles. In this study, we introduce a series of dimethylamino-based ionizable lipidoids (DMA-Lipidoids) engineered for selective mRNA delivery to the spleen. Using a combinatorial approach, we synthesized 48 chemically distinct lipidoids by pairing four DMA-containing amine heads with 12 newly designed hyperbranched tails. Remarkably, lipidoids with tails H228, H226x, H246x, and H446x demonstrated exceptional spleen-targeting efficiency. To refine the lipidoid design, we constructed and screened a secondary library of 36 lipidoids containing DMA analogues. Through this two-round screening process, we identified lipidoids with both high potency and spleen selectivity. The lead candidate, DMA4-H228, achieved precise delivery of ovalbumin mRNA to antigen-presenting cells (APCs), driving interferon-α (IFN α) production and APC activation. This robust immune response effectively inhibited tumor growth. Overall, these innovative DMA-lipidoids demonstrate strong spleen-targeting capabilities, offering a transformative platform for mRNA vaccine development.

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来源期刊

Journal of Controlled Release 医学-化学综合

CiteScore

18.50

自引率

5.60%

发文量

700

审稿时长

39 days

期刊介绍： The Journal of Controlled Release (JCR) proudly serves as the Official Journal of the Controlled Release Society and the Japan Society of Drug Delivery System. Dedicated to the broad field of delivery science and technology, JCR publishes high-quality research articles covering drug delivery systems and all facets of formulations. This includes the physicochemical and biological properties of drugs, design and characterization of dosage forms, release mechanisms, in vivo testing, and formulation research and development across pharmaceutical, diagnostic, agricultural, environmental, cosmetic, and food industries. Priority is given to manuscripts that contribute to the fundamental understanding of principles or demonstrate the advantages of novel technologies in terms of safety and efficacy over current clinical standards. JCR strives to be a leading platform for advancements in delivery science and technology.