Serena Omo-Lamai, Yufei Wang, Manthan N Patel, Eno-Obong Essien, Mengwen Shen, Aparajeeta Majumdar, Carolann Espy, Jichuan Wu, Breana Channer, Michael Tobin, Shruthi Murali, Tyler E Papp, Rhea Maheshwari, Liuqian Wang, Liam S Chase, Marco E Zamora, Mariah L Arral, Oscar A Marcos-Contreras, Jacob W Myerson, Christopher A Hunter, Andrew Tsourkas, Vladimir Muzykantov, Igor Brodsky, Sunny Shin, Kathryn A Whitehead, Peter Gaskill, Dennis Discher, Hamideh Parhiz, Jacob S Brenner
Lipid nanoparticles (LNPs) have emerged as the dominant platform for RNA delivery, based on their success in the COVID-19 vaccines and late-stage clinical studies in other indications. However, we and others have shown that LNPs induce severe inflammation, and massively aggravate pre-existing inflammation. Here, using structure-function screening of lipids and analyses of signaling pathways, we elucidate the mechanisms of LNP-associated inflammation and demonstrate solutions. We show that LNPs' hallmark feature, endosomal escape, which is necessary for RNA expression, also directly triggers inflammation by causing endosomal membrane damage...
April 18, 2024: bioRxiv