Xue Lulu, Zhao Gan, Gong Ningqiang, Han Xuexiang, Shepherd Sarah J, Xiong Xinhong, Xiao Zebin, Palanki Rohan, Xu Junchao, Swingle Kelsey L, Warzecha Claude C, El-Mayta Rakan, Chowdhary Vivek, Yoon Il-Chul, Xu Jingcheng, Cui Jiaxi, Shi Yi, Alameh Mohamad-Gabriel, Wang Karin, Wang Lili, Pochan Darrin J, Weissman Drew, Vaughan Andrew E, Wilson James M, Mitchell Michael J
Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Nat Nanotechnol. 2025 Jan;20(1):132-143. doi: 10.1038/s41565-024-01747-6. Epub 2024 Oct 1.
Systemic delivery of messenger RNA (mRNA) for tissue-specific targeting using lipid nanoparticles (LNPs) holds great therapeutic potential. Nevertheless, how the structural characteristics of ionizable lipids (lipidoids) impact their capability to target cells and organs remains unclear. Here we engineered a class of siloxane-based ionizable lipids with varying structures and formulated siloxane-incorporated LNPs (SiLNPs) to control in vivo mRNA delivery to the liver, lung and spleen in mice. The siloxane moieties enhance cellular internalization of mRNA-LNPs and improve their endosomal escape capacity, augmenting their mRNA delivery efficacy. Using organ-specific SiLNPs to deliver gene editing machinery, we achieve robust gene knockout in the liver of wild-type mice and in the lungs of both transgenic GFP and Lewis lung carcinoma (LLC) tumour-bearing mice. Moreover, we showed effective recovery from viral infection-induced lung damage by delivering angiogenic factors with lung-targeted Si-N14 LNPs. We envision that our SiLNPs will aid in the clinical translation of mRNA therapeutics for next-generation tissue-specific protein replacement therapies, regenerative medicine and gene editing.
使用脂质纳米颗粒（LNP）进行信使核糖核酸（mRNA）的全身递送以实现组织特异性靶向具有巨大的治疗潜力。然而，可电离脂质（类脂质）的结构特征如何影响其靶向细胞和器官的能力仍不清楚。在此，我们设计了一类具有不同结构的基于硅氧烷的可电离脂质，并制备了掺入硅氧烷的LNP（SiLNP），以控制体内mRNA向小鼠肝脏、肺和脾脏的递送。硅氧烷部分增强了mRNA-LNP的细胞内化，并提高了它们的内体逃逸能力，从而增强了它们的mRNA递送效率。通过使用器官特异性SiLNP递送基因编辑工具，我们在野生型小鼠的肝脏以及转基因绿色荧光蛋白（GFP）小鼠和携带Lewis肺癌（LLC）肿瘤小鼠的肺中实现了强大的基因敲除。此外，我们通过用肺靶向的Si-N14 LNP递送血管生成因子，显示出从病毒感染诱导的肺损伤中有效恢复。我们设想，我们的SiLNP将有助于mRNA治疗药物用于下一代组织特异性蛋白质替代疗法、再生医学和基因编辑的临床转化。
