Biological Nanoparticle Fusion with Cell-Membrane Mimics

Research Project, 2023 – 2026

Lipid nanoparticles (LNPs) designed for oligonucleotide delivery, as those used in the mRNA vaccines that have helped mitigate the recent pandemic, have a surprisingly low capacity to delivery functional genetic material, a few percent at best. Yet, there is little understanding of the molecular origin of this low efficiency. The route we will take to help answering this questions takes its base in our internationally recognized expertise in developing state-of-the-art surface-based analytical tools, with the biological and pharmaceutical relevance of the method development being ensured by working in a broad interdisciplinary network. Specifically, this proposal is focused on the further development of surface-sensitive optical microscopy concepts to establish key correlations between the physicochemical properties of individual LNPs and their capacity to fuse with endosomal membranes – the process that is expected to be the primery limiting step in functional oligonucleotide delivery. This way, we will advance the understanding of how LNPs interact with endosomal membranes, which will in turn guide improved designs of LNPs for medical intervantions beyond vaccines. This proposal also puts us in a favorable position to establish a new surface-sensitive microscopy concept that is likely to have broad impact beyond the phenomena put in prime focus, including basic biological nanoparticle research, diagnostics and nanosafety applications.