Vlasova K Yu, Kerr A, Pennock N D, Jozic A, Sahel D K, Gautam M, Murthy N T V, Roberts A, Ali M W, MacDonald K D, Walker J M, Luxenhofer R, Sahay G
Department of Pharmaceutical Sciences, College of Pharmacy at Oregon State University, Corvallis, OR, USA.
Soft Matter Chemistry, Department of Chemistry and Helsinki Institute of Sustainability Science, Faculty of Science, University of Helsinki, Helsinki, Finland.
Nat Commun. 2025 Apr 29;16(1):4021. doi: 10.1038/s41467-025-59136-z.
We present an efficient method for synthesizing cationic poly(ethylene imine) derivatives using the multicomponent split-Ugi reaction to create a library of functional ionizable lipopolymers. Here we show 155 polymers, formulated into polyplexes, to establish structure-activity relationships essential for endosomal escape and transfection. A lead structure is identified, and lipopolymer-lipid hybrid nanoparticles are developed to deliver mRNA to lung endothelium and immune cells, including T cells, with low in vivo toxicity. These nanoparticles show significant improvements in mRNA delivery to the lung compared to in vivo-JetPEI® and demonstrate effective delivery of therapeutic mRNA(s) of various sizes. IL-12 mRNA-loaded nanoparticles delay Lewis Lung cancer progression, while human CFTR mRNA restores CFTR protein function in CFTR knockout mice. Additionally, we demonstrate in vivo CRISPR-Cas9 mRNA delivery, achieving gene editing in lung tissue and successful PD-1 knockout in T cells in mice. These results highlight the platform's potential for systemic gene therapy delivery.
我们提出了一种高效的方法，利用多组分拆分-Ugi反应合成阳离子聚（乙烯亚胺）衍生物，以创建一个功能性可电离脂质聚合物文库。在此，我们展示了155种配制成多聚体的聚合物，以建立对内涵体逃逸和转染至关重要的构效关系。确定了一种先导结构，并开发了脂质聚合物-脂质杂化纳米颗粒，以低体内毒性将mRNA递送至肺内皮细胞和免疫细胞，包括T细胞。与体内使用的JetPEI®相比，这些纳米颗粒在向肺部递送mRNA方面有显著改善，并证明能有效递送各种大小的治疗性mRNA。负载IL-12 mRNA的纳米颗粒可延缓Lewis肺癌进展，而人CFTR mRNA可在CFTR基因敲除小鼠中恢复CFTR蛋白功能。此外，我们展示了体内CRISPR-Cas9 mRNA递送，在小鼠肺组织中实现了基因编辑，并成功敲除了T细胞中的PD-1。这些结果突出了该平台在全身基因治疗递送方面的潜力。
