Self‐Degradable Lipid‐Like Materials Based on “Hydrolysis accelerated by the intra‐Particle Enrichment of Reactant (HyPER)” for Messenger RNA Delivery,Advanced Functional Materials

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Self‐Degradable Lipid‐Like Materials Based on “Hydrolysis accelerated by the intra‐Particle Enrichment of Reactant (HyPER)” for Messenger RNA Delivery
Advanced Functional Materials ( IF 18.5 ) Pub Date : 2020-06-23 , DOI: 10.1002/adfm.201910575
Hiroki Tanaka ₁ , Tatsunari Takahashi ₁ , Manami Konishi ₁ , Nae Takata ₁ , Masaki Gomi ₁ , Daiki Shirane ₁ , Ryo Miyama ₁ , Shinya Hagiwara ₁ , Yuki Yamasaki ₁ , Yu Sakurai ₁ , Keisuke Ueda ₂ , Kenjirou Higashi ₂ , Kunikazu Moribe ₂ , Eiji Shinsho ₃ , Ruka Nishida ₃ , Kaori Fukuzawa _{3,

4} , Etsuo Yonemochi ₃ , Koji Okuwaki ₅ , Yuji Mochizuki _{4,

5} , Yuta Nakai ₆ , Kota Tange ₆ , Hiroki Yoshioka ₆ , Shinya Tamagawa ₆ , Hidetaka Akita ₁

Affiliation

RNA‐based therapeutics is a promising approach for curing intractable diseases by manipulating various cellular functions. For eliciting RNA (i.e., mRNA and siRNA) functions successfully, the RNA in the extracellular space must be protected and it must be delivered to the cytoplasm. In this study, the development of a self‐degradable lipid‐like material that functions to accelerate the collapse of lipid nanoparticles (LNPs) and the release of RNA into cytoplasm is reported. The self‐degradability is based on a unique reaction “Hydrolysis accelerated by intra‐Particle Enrichment of Reactant (HyPER).” In this reaction, a disulfide bond and a phenyl ester are essential structural components: concentrated hydrophobic thiols that are produced by the cleavage of the disulfide bonds in the LNPs drive an intraparticle nucleophilic attack to the phenyl ester linker, which results in further degradation. An oleic acid‐scaffold lipid‐like material that mounts all of these units (ssPalmO‐Phe) shows superior transfection efficiency to nondegradable or conventional materials. The insertion of the aromatic ring is unexpectedly revealed to contribute to the enhancement of endosomal escape. Since the intracellular trafficking is a sequential process that includes cellular uptake, endosomal escape, the release of mRNA, and translation, the improvement in each process synergistically enhances the gene expression.

中文翻译：

基于“通过颗粒内富集反应物（HyPER）加速水解”的自降解脂质样材料，用于信使RNA的递送

基于RNA的疗法是通过控制各种细胞功能来治愈顽固性疾病的有前途的方法。为了成功引发RNA（即mRNA和siRNA）功能，必须保护细胞外空间中的RNA，并将其传递到细胞质中。在这项研究中，报道了一种可降解脂质样材料的发展，该材料具有加速脂质纳米颗粒（LNPs）崩溃和RNA释放到细胞质中的作用。自降解性基于独特的反应“通过颗粒内富集反应物（HyPER）加速水解”。在该反应中，二硫键和苯酯是必不可少的结构成分：LNP中二硫键断裂产生的高浓度疏水性硫醇会驱使颗粒内的亲核分子攻击苯酯连接基，从而进一步降解。安装了所有这些单元的油酸支架脂质样材料（ssPalmO-Phe）表现出比不可降解或常规材料优异的转染效率。出人意料地揭示出芳环的插入有助于内体逃逸的增强。由于细胞内运输是包括细胞摄取，内体逃逸，mRNA释放和翻译的顺序过程，因此每个过程中的改善都协同增强了基因表达。安装了所有这些单元的油酸支架脂质样材料（ssPalmO-Phe）表现出比不可降解或常规材料优异的转染效率。出人意料地揭示出芳环的插入有助于内体逃逸的增强。由于细胞内运输是包括细胞摄取，内体逃逸，mRNA释放和翻译的顺序过程，因此每个过程中的改善都协同增强了基因表达。安装了所有这些单元的油酸支架脂质样材料（ssPalmO-Phe）表现出比不可降解或常规材料优异的转染效率。出人意料地揭示出芳环的插入有助于内体逃逸的增强。由于细胞内运输是包括细胞摄取，内体逃逸，mRNA释放和翻译的顺序过程，因此每个过程中的改善都协同增强了基因表达。

更新日期：2020-08-19

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