Omo-Lamai Serena, Wang Yufei, Patel Manthan N, Milosavljevic Aleksa, Zuschlag Daniel, Poddar Subhajit, Wu Jichuan, Wang Liuqian, Dong Fengyi, Espy Carolann, Majumder Aparajeeta, Essien Eno-Obong, Shen Mengwen, Channer Breana, Papp Tyler E, Tobin Michael, Maheshwari Rhea, Jeong Sumin, Patel Sofia, Shah Anit, Murali Shruthi, Chase Liam S, Zamora Marco E, Arral Mariah L, Marcos-Contreras Oscar A, Myerson Jacob W, Hunter Christopher A, Discher Dennis, Gaskill Peter J, Tsourkas Andrew, Muzykantov Vladimir R, Brodsky Igor, Shin Sunny, Whitehead Kathryn A, Parhiz Hamideh, Katzen Jeremy, Miner Jonathan J, Trauner Dirk, Brenner Jacob S
Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, USA.
Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Nat Nanotechnol. 2025 Aug 11. doi: 10.1038/s41565-025-01974-5.
Lipid nanoparticles (LNPs) have emerged as the dominant platform for RNA delivery, but they induce severe inflammation. Here we show that LNPs' hallmark feature, endosomal escape, which is necessary for RNA expression, also triggers inflammation by causing endosomal membrane damage. Large, irreparable, endosomal holes are recognized by cytosolic proteins called galectins, which regulate downstream inflammation. We find that inhibition of galectins abrogates LNP-associated inflammation, both in vitro and in vivo. Moreover, we show that a unique class of ionizable lipids can create smaller endosomal holes, reparable by the endosomal sorting complex required for transport (ESCRT) pathway. Such lipids can produce high expression from cargo messenger RNA with minimal inflammation. Finally, we show that both galectin inhibition or ESCRT-recruiting ionizable lipids allow for treatment of highly inflammatory disease models by therapeutic mRNAs. These strategies should lead to safer non-inflammatory LNPs that can be generally used to treat inflammatory diseases.
脂质纳米颗粒（LNPs）已成为RNA递送的主要平台，但它们会引发严重炎症。我们在此表明，LNPs的标志性特征——内体逃逸（这是RNA表达所必需的），也会通过导致内体膜损伤而引发炎症。称为半乳糖凝集素的胞质蛋白可识别大的、无法修复的内体孔，这些蛋白会调节下游炎症反应。我们发现，抑制半乳糖凝集素可在体外和体内消除与LNP相关的炎症。此外，我们表明，一类独特的可电离脂质可形成较小的内体孔，这些孔可通过内体转运所需的分选复合体（ESCRT）途径修复。这类脂质能够在炎症最小的情况下从货物信使RNA产生高表达。最后，我们表明，抑制半乳糖凝集素或招募ESCRT的可电离脂质都可通过治疗性mRNA治疗高度炎症性疾病模型。这些策略应能产生更安全的非炎性LNPs，可普遍用于治疗炎症性疾病。
