Fused, Not Coated: The Protein Corona on Ionizable Lipid Nanoparticles, from Biophysical Curiosity to Clinical Design Parameter
Hossein Nejadnik, Amanda M. Murray, Pooneh Memar Ardestani, Michael J. Mitchell, Morteza MahmoudiAbstract
No lipid nanoparticle (LNP) arrives in the body as the particle a chemist made. Within moments of entering a biological fluid, it is stripped of that designed identity and reclothed by the proteins and lipoproteins it collides with there, and it is this improvised second identity that interacts with biosystems and determines where the particle goes, how long it circulates, whether the immune system treats it as a threat, and how much of its cargo reaches the cytosol. LNPs have ridden this reality from a niche delivery platform to the backbone of an entire therapeutic class, carrying siRNA and mRNA into patients on a global scale, yet the framework used to describe this in vivo transformation, the protein corona, was built for rigid, inorganic nanoparticles and fits LNPs poorly. These are not inert cores decorated with protein; they are dynamic, fusogenic lipid assemblies that trade material with the apolipoproteins that coat them, a behavior apolipoprotein structural biology has documented for over two decades but that corona science only recently recognized as central to how the LNP corona itself forms. This Perspective traces that history─from the polystyrene-bead origins of corona science, through the apolipoprotein E (ApoE)-LDL receptor pathway that governs LNP hepatic tropism, to the growing case that LNP coronas arise through lipoprotein fusion rather than classical protein adsorption─and argues that clinical translation now depends on treating the corona as a design parameter rather than an after-the-fact explanation: resolving how LNPs physically acquire their corona, distinguishing which apolipoprotein proteoforms, not just which proteins, drive delivery versus clearance, building corona characterization fast enough to sit inside a development timeline, and connecting the personalized, disease-specific corona to real dosing and safety decisions instead of leaving it as a diagnostic curiosity.