Sahoo Dipankar, Atochina-Vasserman Elena N, Lu Juncheng, Maurya Devendra S, Ona Nathan, Vasserman Jessica A, Ni Houping, Berkihiser Sydni, Park Wook-Jin, Weissman Drew, Percec Virgil
Roy & Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323, United States.
Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
Biomacromolecules. 2025 Jan 13;26(1):726-737. doi: 10.1021/acs.biomac.4c01599. Epub 2024 Dec 17.
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 p of the IAJDs and through flexibility, the stability of the DNPs, highlighting their extraordinarily important role in effective targeted delivery.
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包含可电离脂质、磷脂、胆固醇和聚乙二醇（PEG）共轭脂质，通过静脉或肌肉注射将COVID-19疫苗的mRNA递送至肝脏。2021年，我们阐述了单组分可电离两亲性Janus树枝状大分子（IAJDs）实现mRNA的靶向递送。简化的合成和组装过程使得能够快速筛选IAJDs以进行发现。IAJDs一级结构在活性方面的作用经初步研究表明，可电离胺（IA）、序列以及亲水和疏水结构域的结构对于体内靶向递送很重要。在此，我们研究基于季戊四醇的IAJDs中IA与疏水结构域之间连接子长度的作用。连接子长度通过诱导效应决定IA的位置和IAJDs的pKa，并通过柔韧性决定DNPs的稳定性，突出了它们在有效靶向递送中极其重要的作用。
