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 Si₅-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） 系统递送信使 RNA （mRNA） 用于组织特异性靶向具有巨大的治疗潜力。然而，可电离脂质 （lipidoids） 的结构特征如何影响它们靶向细胞和器官的能力仍不清楚。在这里，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，并配制了硅氧烷掺入的 LNP （SiLNP） 来控制小鼠体内 mRNA 向肝脏、肺和脾脏的递送。硅氧烷部分增强 mRNA-LNP 的细胞内化并提高其内体逃逸能力，从而增强其 mRNA 递送功效。使用器官特异性 SiLNP 递送基因编辑机制，我们在野生型小鼠的肝脏以及转基因 GFP 和 Lewis 肺癌 （LLC） 荷瘤小鼠的肺部实现了稳健的基因敲除。此外，我们发现通过用肺靶向 Si 5-N14 LNP 递送血管生成因子，可以有效地恢复病毒感染诱导的肺损伤。我们设想我们的 SiLNP 将有助于 mRNA 疗法的临床转化，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。