Narasipura Eshan A, Ma Yutian, Tiwade Palas Balakdas, VanKeulen-Miller Rachel, Fung Vincent, Fenton Owen S
Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
Bioconjug Chem. 2025 Jan 15;36(1):54-65. doi: 10.1021/acs.bioconjchem.4c00419. Epub 2024 Dec 20.
mRNA lipid nanoparticles (LNPs) are a powerful technology that are actively being investigated for their ability to prevent, treat, and study disease. However, a major limitation remains: achieving extrahepatic mRNA expression. The development of new carriers could enable the expression of mRNA in non-liver targets, thus expanding the utility of mRNA-based medicines. In this study, we use a combination of chemoinformatic-guided material synthesis and design of experiment optimization for the development of a spleen-expressing lipid nanoparticle (SE-LNP). We begin with the synthesis of a novel cholesterol derivative followed by SE-LNP formulation and design of experiment-guided optimization to identify three lead SE-LNPs. We then evaluate their delivery mechanism, biodistribution, and protein expression in mice, ultimately achieving spleen-preferential expression. The goal of this paper is thus to create LNPs that preferentially express mRNA in the spleen upon intravenous delivery, demonstrating the potential of LNPs to modulate gene expression in extrahepatic tissues for disease treatment.
信使核糖核酸脂质纳米颗粒（LNPs）是一项强大的技术，目前正因其预防、治疗和研究疾病的能力而受到积极研究。然而，一个主要限制仍然存在：实现肝外信使核糖核酸表达。新型载体的开发能够使信使核糖核酸在非肝脏靶点表达，从而扩大基于信使核糖核酸的药物的应用范围。在本研究中，我们结合化学信息学引导的材料合成和实验设计优化来开发一种脾脏表达脂质纳米颗粒（SE-LNP）。我们首先合成一种新型胆固醇衍生物，随后进行SE-LNP制剂的制备以及实验设计引导的优化，以确定三种先导SE-LNP。然后我们评估它们在小鼠体内的递送机制、生物分布和蛋白质表达，最终实现脾脏优先表达。因此，本文的目标是创建在静脉注射后能在脾脏中优先表达信使核糖核酸的LNPs，证明LNPs在调节肝外组织基因表达以治疗疾病方面的潜力。
