Precision Oligo(ethylene glycol) Interfaces Shape Nanoparticle Biodistribution through In Vivo Protein Corona

Understanding the interplay between nanoparticle surface chemistry and biological context in shaping in vivo fate remains a central challenge in nanomedicine. Although protein corona formation is widely recognized as a key mediator of nanoparticle-host interactions, the extent to which specific corona components influence organ-level biodistribution remains unclear. Here, to minimize the confounding effect of PEG dispersity on corona assembly, we constructed chemically uniform nanoparticle interfaces using precision oligo(ethylene glycol) ligands with defined chain length and terminal functionality. Using Co-doped Fe₃O₄ nanoparticles together with a magnetic-assisted nanoparticle sorting workflow, we improved recovery of nanoparticle-associated protein coronas and established optimized conditions for in vivo corona analysis. By integrating pathological animal models, quantitative proteomics, reconstructed coronas based on proteins identified in vivo, genetic ablation, and pharmacological inhibition, we established an experimental framework linking corona composition to organ distribution. Within this framework, a simplified four-protein reconstructed corona containing ApoE, ApoA-I, C3, and C1qA showed that the combination and relative abundance of a limited set of key corona proteins can partly explain organ-associated nanoparticle uptake patterns. Importantly, these corona signatures were also associated with organ-level biodistribution in vivo and helped explain distribution shifts under pathological conditions. Together, these findings support a corona-based framework linking nanoparticle interface chemistry and biological state to organ-level distribution under physiological and pathological conditions.