Distinct Inflammatory Programs Underlie the Intramuscular Lipid Nanoparticle Response 2267321

Abstract

Abstract Introduction Developments in mRNA Lipid nanoparticle (mRNA/LNP) technologies have heralded a new era of both vaccines and therapeutics, raising questions about their immunogenicity. While robust immune responses are required for effective vaccination, aberrant inflammation can hinder efficacy of RNA therapeutics. Understanding mechanisms underlying these disparate immunological responses is critical for development of safe and effective delivery systems for vaccines and gene therapies. Methods We sought to understand if ionizable lipid chemistry determines an LNP’s immunogenic potential in vivo as well as the underlying cellular mechanisms. To this end we employed a combination of flow cytometric, transcriptomic, and serological techniques to understand the muscle tissue restricted immunomodulatory mechanisms of LNPs harboring different lipid chemistries. To determine upstream regulators we integrated transcriptomic, cell reporter and genomic screening studies. Results We find that ionizable lipid chemistry determines magnitude of inflammatory gene expression locally within injected muscle. Additionally, LNPs induce rapid and robust neutrophil infiltration into injected muscle and ionizable lipid chemistry determines the magnitude of infiltration. We find that systemically ionizable lipid chemistry and RNA immunogenicity act synergistically within critical antigen presenting cells. Ionizable lipid chemistry determines the efficiency that cDC2 and B cells are transfected as well as their subsequent activation. Conclusion Based on these data we propose a classification of ionizable lipids based on their acute immunomodulatory capacity: Class A inflammatory and Class B non-inflammatory. Funding Source n/a Topic Categories Vaccines and Immunotherapy (VAC)