以季戊四醇为基础的单组分可电离两亲性两面树形大分子体内Luc-mRNA传递的主要结构和活性的完全阐明。

IF 5.5 2区化学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biomacromolecules Pub Date : 2025-01-13 DOI:10.1021/acs.biomac.4c01599

Dipankar Sahoo , Elena N. Atochina-Vasserman , Juncheng Lu , Devendra S. Maurya , Nathan Ona , Jessica A. Vasserman , Houping Ni , Sydni Berkihiser , Wook-Jin Park , Drew Weissman , Virgil Percec

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引用次数: 0

摘要

四组分脂质纳米颗粒（LNPs）和病毒载体是mRNA疫苗和治疗药物递送的关键。LNPs含有可电离脂质、磷脂、胆固醇和聚乙二醇（PEG）偶联脂质，并通过静脉注射或肌肉注射将用于COVID-19疫苗的mRNA传递到肝脏。在2021年，我们阐述了单组分电离的两亲性Janus树突状分子（IAJDs）可以靶向递送mRNA。简化的合成和组装过程允许快速筛选IAJD的发现。初步研究表明，IAJDs的一级结构在活性中的作用表明，可电离胺（ionizable amine， IA）、亲疏水结构域的序列和结构对于体内靶向递送很重要。在此，我们研究了季戊四醇基iajd的IA和疏水结构域之间的互连连接体长度的作用。通过诱导效应，连接体长度决定了iajd的IA和pKa的位置，通过灵活性决定了DNPs的稳定性，突出了它们在有效靶向递送中的异常重要作用。

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Toward a Complete Elucidation of the Primary Structure–Activity in Pentaerythritol-Based One-Component Ionizable Amphiphilic Janus Dendrimers for In Vivo Delivery of Luc-mRNA

Four-component lipid nanoparticles (LNPs) and viral vectors are key for mRNA vaccine and therapeutics delivery. LNPs contain ionizable lipids, phospholipids, cholesterol, and polyethylene glycol (PEG)-conjugated lipids and deliver mRNA for COVID-19 vaccines to liver when injected intravenously or intramuscularly. In 2021, we elaborated one-component ionizable amphiphilic Janus dendrimers (IAJDs) accessing targeted delivery of mRNA. Simplified synthesis and assembly processes allow for rapid IAJD screening for discovery. The role of the primary structure of IAJDs in activity indicated, with preliminary investigations, that ionizable amine (IA), sequence, and architecture of hydrophilic and hydrophobic domains are important for in vivo targeted delivery. Here, we study the role of the interconnecting linker length between the IA and the hydrophobic domain of pentaerythritol-based IAJDs. The linker length determines, through inductive effects, the position of the IA and the pK _a of the IAJDs and through flexibility, the stability of the DNPs, highlighting their extraordinarily important role in effective targeted delivery.

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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.