Surface Plasmon Resonance Based Binding Characterization for Screening RNA-Loaded Lipid Nanoparticles (LNPs): Exploring Species Cross-Reactivity in LNP-Apolipoprotein E Interactions.

Lipid nanoparticles (LNPs) are an essential delivery platform for nucleic acid payloads that are susceptible to degradation or elimination. Upon administration, a biomolecular corona composed of serum proteins forms around the LNP surface, which is crucial for tissue targeting and biodistribution. One essential protein that drives the distribution of LNPs is apolipoprotein E (ApoE). In this work, we used ApoE as a model protein to probe LNP-protein interactions utilizing a surface plasmon resonance (SPR) interaction assay comparable to the conventional quartz crystal microbalance with dissipation (QCM-D) assay. We employed two LNP formulations with or without payload and various ApoE homologs to establish the SPR method as an in vitro tool to screen LNP formulations and explore species cross-reactivity in LNP-protein interactions. Two binding models were applied to capture the difference in binding behaviors of different ApoE homologs in terms of relative binding response and association kinetics.