Replacing PEG-Lipid with Amphiphilic Polycarbonates in mRNA-Loaded Lipid Nanoparticles: Impact of Polycarbonate Structure on Physicochemical and Transfection Properties.

IF 5.5 2区化学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biomacromolecules Pub Date : 2025-05-10 DOI:10.1021/acs.biomac.5c00088

Dao Thi Hong Le, Chuan Yang, Yue Zhang, Gui Zhao, Melgious J Y Ang, Ki Hyun Bae, James H P Hui, James L Hedrick, Yi Yan Yang

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引用次数: 0

Abstract

Since the remarkable breakthrough of COVID-19 mRNA vaccines, lipid nanoparticles (LNPs) have gained substantial attention as the most cutting-edge clinical formulations for mRNA delivery. PEGylated lipid (PEG-lipid) has been regarded as an essential constituent of LNPs that helps to prolong their systemic circulation by preventing particle aggregation in the blood and sequestration by the mononuclear phagocyte system. Herein, we synthesized a series of mRNA-loaded nanoparticles by replacing ALC-0159 (a PEG-lipid used in the Comirnaty formulation) with amphiphilic PEG-polycarbonate diblock copolymers (PC-HNPs). Interestingly, variations of polycarbonate block length and structure significantly influenced mRNA encapsulation efficiency, transfection potency, colloidal stability, and PEG shedding rate of PC-HNPs. In vivo and ex vivo bioluminescence imaging revealed that upon subcutaneous administration in mice, the leading candidate PC3-HNP achieved lymph node accumulation comparable to that of the conventional ALC-0159-based LNP formulation while avoiding undesirable liver accumulation. Our findings may provide valuable information for the construction of next-generation nanocarriers for effective mRNA delivery.

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用两亲性聚碳酸酯取代含mrna的脂质纳米颗粒中的peg -脂质：聚碳酸酯结构对理化和转染性能的影响。

自COVID-19 mRNA疫苗取得重大突破以来，脂质纳米颗粒（LNPs）作为最先进的mRNA递送临床配方受到了广泛关注。聚乙二醇化脂质（peg -脂质）被认为是LNPs的重要组成部分，通过防止颗粒在血液中聚集和被单核吞噬细胞系统隔离，有助于延长LNPs的体循环。在此，我们用两亲性peg -聚碳酸酯二嵌段共聚物（PC-HNPs）取代ALC-0159 （Comirnaty配方中使用的peg -脂质）合成了一系列装载mrna的纳米颗粒。有趣的是，聚碳酸酯块长度和结构的变化显著影响了PC-HNPs的mRNA包封效率、转染效力、胶体稳定性和PEG脱落率。体内和离体生物发光成像显示，在小鼠皮下给药后，主要候选PC3-HNP实现了与传统的基于alc -0159的LNP配方相当的淋巴结积聚，同时避免了不良的肝脏积聚。我们的研究结果可能为构建下一代有效递送mRNA的纳米载体提供有价值的信息。

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

Biomacromolecules 化学-高分子科学

CiteScore

10.60

自引率

4.80%

发文量

417

审稿时长

1.6 months

期刊介绍： Biomacromolecules is a leading forum for the dissemination of cutting-edge research at the interface of polymer science and biology. Submissions to Biomacromolecules should contain strong elements of innovation in terms of macromolecular design, synthesis and characterization, or in the application of polymer materials to biology and medicine. Topics covered by Biomacromolecules include, but are not exclusively limited to: sustainable polymers, polymers based on natural and renewable resources, degradable polymers, polymer conjugates, polymeric drugs, polymers in biocatalysis, biomacromolecular assembly, biomimetic polymers, polymer-biomineral hybrids, biomimetic-polymer processing, polymer recycling, bioactive polymer surfaces, original polymer design for biomedical applications such as immunotherapy, drug delivery, gene delivery, antimicrobial applications, diagnostic imaging and biosensing, polymers in tissue engineering and regenerative medicine, polymeric scaffolds and hydrogels for cell culture and delivery.