LIPION: Integrated Neutron and X-ray Instrumentation for Lipid and Ionizable Nanoparticle Systems

Research Project, 2026 – 2031

LIPION combines experimental and computational developments to study lipid mesophases, bilayers and lipid nanoparticles (LNPs). Building on recent advances in small-angle scattering and reflectometry, we will develop novel neutron instrumentation and data-driven analysis frameworks that provide molecular-level insight into pH-dependent structural transitions of LNPs during the process of endosomal escape. The project is structured into three work packages that cover instrumentation development, model system studies, and investigation of fusion processes. Firstly, we will design and implement a neutron cavity resonator to improve signal-to-noise ratios and minimize required sample volumes. In parallel, we will establish inverse modeling frameworks that integrate molecular dynamics simulations with machine learning to reconstruct molecular structures directly from experimental scattering data. Next, we will apply advanced NR techniques to study supported and floating bilayers that mimic endosomal membranes, and their interactions with LNPs. Finally, we investigate pH-dependent fusion of LNPs with endosomal membrane/vesicle mimics using NR, SANS, and SAXS. Our approach enables a deeper mechanistic understanding of how LNPs undergo pH-dependent structural transitions and fuse with anionic model membranes. The methodologies and software tools developed in this project will be broadly applicable, facilitating the study of lipid systems and nanoparticle-based delivery platforms.