Miktoarm Star-polypept(o)ide-Based Polyion Complex Micelles for the Delivery of Large Nucleic Acids

IF 5.5 2区化学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Biomacromolecules Pub Date : 2024-09-18 DOI:10.1021/acs.biomac.4c00695

David Schwiertz, Jennifer Angelina, Heyang Zhang, Matthias Barz

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Abstract

Miktoarm star polymers exhibit a captivating range of physicochemical properties, setting them apart from their linear counterparts. This study devised a synthetic pathway to synthesize cationic miktoarm stars utilizing polypept(o)ides (PeptoMiktoStars), comprising 3 or 6 polysarcosine (pSar) arms (AB_3×100, AB_6×50, overall 300) for shielding and a cross-linkable poly(S-ethylsulfonyl-l-homocysteine) (pHcy(SO₂Et)₂₀) block and a poly(l-lysine) ((pLys)₂₀) block for nucleic acid complexation. Precise control over the DP_n and narrow molecular weight distributions (D̵ ≈ 1.2) were achieved for both structures. Both PeptoMiktoStars efficiently complexed mRNA and pDNA into polyion complex micelles (PICMs). AB₆–PICMs provided modest (mRNA) to high (pDNA) stability against glutathione and heparin sulfate (HS), while even cross-linked AB₃–PICMs were susceptible to HS. All PICMs delivered pDNA and mRNA into D1 cells (over 80%) and Jurkat T cells (over 50%) in vitro. Despite payload- and cell-dependency, AB₃ showed overall higher transfection efficiency, while AB₆ demonstrated better shielding and enhanced stability.

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Miktoarm 星型多肽（o）ide 基多离子复合物胶束用于递送大分子核酸

米克托臂星型聚合物表现出一系列迷人的物理化学特性，使其有别于线型聚合物。这项研究设计了一种合成途径，利用多肽（o）ides（PeptoMiktoStars）合成阳离子米克托臂星型聚合物，多肽（o）ides 由 3 或 6 个聚肌氨酸（pSar）臂（AB3×100、AB3×100、AB6×50，总计 300）进行屏蔽，以及一个可交联的聚(S-乙基磺酰基-l-高半胱氨酸) (pHcy(SO2Et)20) 嵌段和一个聚(l-赖氨酸) ((pLys)20)嵌段进行核酸复合。两种结构都实现了对 DPn 的精确控制和较窄的分子量分布（D̵ ≈ 1.2）。两种 PeptoMiktoStars 都能将 mRNA 和 pDNA 有效地复合到多离子复合胶束（PICM）中。AB6-PICM 对谷胱甘肽和硫酸肝素（HS）的稳定性（mRNA）从低到高不等，而即使是交联的 AB3-PICM 也易受 HS 影响。所有 PICM 在体外都能将 pDNA 和 mRNA 送入 D1 细胞（80% 以上）和 Jurkat T 细胞（50% 以上）。尽管有效载荷和细胞依赖性不同，但 AB3 显示出更高的总体转染效率，而 AB6 则显示出更好的屏蔽性和更高的稳定性。

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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.