High-density brush-shaped polymer lipids reduce anti-PEG antibody binding for repeated administration of mRNA therapeutics

IF 37.2 1区 材料科学 Q1 CHEMISTRY, PHYSICAL
Yufen Xiao, Xizhen Lian, Yehui Sun, Yun-Chieh Sung, Amogh Vaidya, Zexiang Chen, Ankit Gupta, Sumanta Chatterjee, Lining Zheng, Erick Guerrero, Xu Wang, Lukas Farbiak, Yangyang Yang, Marc I. Diamond, Cecilia Leal, Jeffrey G. McDonald, Daniel J. Siegwart
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引用次数: 0

Abstract

Messenger RNA lipid-nanoparticle-based therapies represent an emerging class of medicines for a variety of applications. However, anti-poly(ethylene glycol) (anti-PEG) antibodies generated by widely used PEGylated medicines and lipid nanoparticles hinder therapeutic efficacy upon repeated dosing. Here we report the chemical design, synthesis and optimization of high-density brush-shaped polymer lipids that reduce anti-PEG antibody binding to improve protein production consistency in repeated dosing. Brush-shaped polymer lipid parameters, including side chain length, degree of polymerization, anchor alkyl length and surface regimes on lipid nanoparticles modulate anti-PEG antibody binding affinity and control their blood circulation pharmacokinetics. Compared to widely used 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000, lipid nanoparticles containing brush-shaped polymer lipids generate superior therapeutic outcomes in protein replacement therapy and genome editing models, reformulating structure–activity guidelines for the design of PEG lipid substitutes. Overall, these findings contribute to the general effort in the development of lipid nanoparticles with low immunogenicity to overcome current roadblocks to nucleic acid medicines.

Abstract Image

基于信使 RNA 脂质纳米粒子的疗法是一类新兴的药物,可用于多种用途。然而,广泛使用的 PEG 化药物和脂质纳米颗粒产生的抗聚(乙二醇)(anti-PEG)抗体会妨碍重复给药的疗效。在此,我们报告了高密度刷状聚合物脂质的化学设计、合成和优化,这种脂质可减少抗 PEG 抗体的结合,从而提高重复给药时蛋白质生产的一致性。刷状聚合物脂质的参数,包括侧链长度、聚合度、锚烷基长度和脂质纳米颗粒的表面制度,可调节抗 PEG 抗体的结合亲和力并控制其血液循环药代动力学。与广泛使用的 1,2-二肉豆蔻酰基-rac-甘油-3-甲氧基聚乙二醇-2000 相比,含有刷状聚合物脂质的脂质纳米粒在蛋白质替代疗法和基因组编辑模型中产生了更好的治疗效果,重新制定了 PEG 脂质替代品设计的结构-活性指南。总之,这些发现有助于开发免疫原性低的脂质纳米粒子,以克服目前核酸药物的障碍。
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来源期刊
Nature Materials
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.
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