Amphiphilic Polyaspartamide Derivatives with Cholesterol Introduction Enhanced Ex Vivo mRNA Transfection Efficiency to Natural Killer Cells

IF 5.4 2区化学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Biomacromolecules Pub Date : 2025-02-10 DOI:10.1021/acs.biomac.4c01411

David Koam , Ha Yeon Park , Dong Sun Kim , Hyeong Jin Kwon , Yan Lee , Kyobum Kim , Mitsuru Naito , Hyun Jin Kim

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Abstract

Engineered natural killer (NK) cells eliminate cancer cells by overexpressing a chimeric antigen receptor, producing highly efficient and safe NK cell therapies. This study investigated the polyplex formulation for the fusion protein GreenLantern-natural killer group 2D (NKG2D) mRNA to evaluate its ex vivo delivery efficacy into NK cells, wherein NKG2D on the surface of NK cells recognized its counterpart NKG2D ligands on cancer cells. Amphiphilic polyaspartamide derivatives Chol-PAsp(DET/CHE) were prepared by adding cyclohexylethylamine (CHE) and diethylenetriamine (DET) in the side chains and cholesterol (Chol) at the α-terminus to enhance endosomal escapability and optimize hydrophobicity. Chol-PAsp(DET/CHE) significantly improved mRNA delivery efficacy into NK-92mi cells, explained by increased polyplex stability and improved cellular uptake of mRNA. The NKG2D-overexpressing NK-92mi cells exhibited high anticancer efficacy against human colon cancer cells without affecting the viability of fibroblasts. Therefore, Chol-PAsp(DET/CHE) could be a promising mRNA delivery carrier for the ex vivo engineering of NK cells.

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引入胆固醇的两亲性聚阿斯巴胺衍生物提高了体外mRNA转染自然杀伤细胞的效率。

工程自然杀伤细胞（NK）通过过表达嵌合抗原受体来消除癌细胞，产生高效、安全的NK细胞疗法。本研究研究了融合蛋白GreenLantern-natural killer group 2D (NKG2D) mRNA的复合制剂，以评估其在NK细胞中的体外递送效果，其中NK细胞表面的NKG2D识别癌细胞上的对应NKG2D配体。通过在侧链上加入环己基乙胺（CHE）和二乙烯三胺（DET），在α-端加入胆固醇（Chol），以增强内体逃逸性和优化疏水性，制备了两亲性聚天冬酰胺衍生物胆- pasp （DET/CHE）。choll - pasp （DET/CHE）显著提高了mRNA在NK-92mi细胞中的传递效率，这可以通过增加复合体稳定性和改善细胞对mRNA的摄取来解释。nkg2d过表达的NK-92mi细胞在不影响成纤维细胞活力的情况下，对人结肠癌细胞表现出较高的抗癌效果。因此，choll - pasp （DET/CHE）可能成为NK细胞离体工程mRNA传递载体。

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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.