Peña Álvaro, Heredero Juan, Blandín Beatriz, Mata Elena, De Miguel Diego, Toro Alfonso, Alejo Teresa, Casabona Diego, López Alexandre, Gallego-Lleyda Ana, Pérez-Herrán Esther, Martínez-Oliván Juan, Giménez-Warren Javier
Certest Pharma, Certest Biotec S. L., 50840, San Mateo de Gállego, Zaragoza, Spain.
Commun Chem. 2025 Apr 16;8(1):116. doi: 10.1038/s42004-025-01516-z.
Ionizable lipids are essential components of lipid nanoparticles (LNPs) for efficient mRNA delivery. However, designing them for high protein expression, endosomal escape, and organ targeting is challenging due to complex structure-activity relationships. Here, we present a high-throughput platform for screening ionizable lipids using a two-step, scalable, one-pot reaction. This enabled the synthesis and vivo screening of 91 new lipids, followed by a structure-activity study, leading to the development of CP-LC-0729, which significantly surpasses the MC3 benchmark in protein expression with preliminary studies showing no in vivo toxicity. Additionally, a one-step strategy helped to yield a permanently cationic lipid which was tested in a fifth-lipid formulation, showing a highly selective lung delivery with a 32-fold increase in protein expression in vivo, outperforming current endogenous targeting strategies. All these findings underscore the potential of lipid CP-LC-0729 and our lipid platform in advancing the efficiency and specificity of mRNA delivery systems.
可电离脂质是用于高效mRNA递送的脂质纳米颗粒（LNP）的重要组成部分。然而，由于复杂的构效关系，设计具有高蛋白质表达、内体逃逸和器官靶向性的可电离脂质具有挑战性。在此，我们展示了一个用于筛选可电离脂质的高通量平台，该平台采用两步、可扩展的一锅法反应。这使得能够合成并在体内筛选91种新脂质，随后进行构效研究，从而开发出CP-LC-0729，在蛋白质表达方面显著超过MC3基准，初步研究表明其在体内无毒性。此外，一种一步法策略有助于产生一种永久性阳离子脂质，该脂质在五脂质配方中进行了测试，显示出高度选择性的肺部递送，体内蛋白质表达增加了32倍，优于目前的内源性靶向策略。所有这些发现都强调了脂质CP-LC-0729和我们的脂质平台在提高mRNA递送系统的效率和特异性方面的潜力。
