Metabolic state rewires hepatic delivery of LNP-encapsulated mRNA

Joël Tissink – PhD candidate, Helmholtz Munich; Mariona Estape Senti – Post doctoral researcher, University Medical Center Utrecht; Marcel Fens – Research Associate, Utrecht University; Anja Zeigerer – Department Leader, University Medical Center Mannheim; Raymond Schiffelers – Head CDL Research, UMC Utrecht; Pol Escudé Martinez de Castilla – Post Doctoral researcher, UMC Utrecht

Introduction: Lipid nanoparticles (LNPs) enable efficient systemic mRNA delivery, yet the biological determinants influencing their performance remain poorly defined. Following intravenous administration, LNPs preferentially accumulate in the liver, a metabolically plastic organ sensitive to nutritional state. These physiological shifts may have important consequences for LNP uptake and mRNA delivery efficacy. Building on previous observations linking feeding status to altered hepatic endosomal activity, we examined how feeding status alters hepatic mRNA expression, LNP biodistribution, and trafficking dynamics in vitro and in vivo.