Moving Beyond PEG: Poly(2-oxazolines) and Poly(2-oxazines) Alter the Surface Properties of Lipid Nanoparticles

Nucleic acid carrying lipid nanoparticles have received great attention since the COVID-19 pandemic. To extend their usage to other therapeutic fields, understanding the impact of tuning their components is crucial. Here, we performed all-atom molecular dynamics simulations on lipid nanoparticles coated with hydrophilic poly(2-oxazoline)s and poly(2-oxazine)s, resembling biocompatible substitutes for the gold standard poly(ethylene glycol). Our results show distinctly different interaction profiles, with the alternatives less likely to address ionizable lipids on the outer membrane. The observed changes in nanoparticle surface coverage and membrane properties could influence particle size, protein corona formation and, ultimately, the biological fate in vivo.