Controlled functionalization of cellulose nanocrystals directs polymer-specific protein coronas and immune cell interactions

Polymer coatings are widely used to suppress nonspecific protein adsorption and modulate nanoparticle-cell interactions. However, the biological outcomes of polymer-functionalized nanoparticles remain difficult to predict in complex biological environments because protein corona formation rapidly alters nanoparticle identity. This challenge is particularly pronounced when hydrophobic moieties are incorporated for imaging or therapeutic applications, as they can promote nonspecific interactions at the nano-bio interface. Herein, we establish a modular grafting-to platform based on cellulose nanocrystals (CNCs) that enables systematic comparison of polyethylene glycol (PEG)-based, zwitterionic, and acrylamide-based polymers with controlled grafting density and chain conformation on a common porphyrin-modified surface. We demonstrate that dense polymer brushes reduce nonspecific protein adsorption in single-protein assays. By contrast, all CNC surfaces form dynamic coronas upon exposure to serum proteins, while specific polymer coatings selectively enrich or suppress distinct protein populations. We further demonstrate that polymer-dependent immune cell interactions are substantially reduced following protein corona formation, although differences among polymer chemistries persist. Zwitterionic coatings broadly suppress immune cell interactions, whereas PEG-based coatings preferentially promote interactions with antigen-presenting cells. These findings establish design principles for polymer-functionalized nanoparticles with specific immune cell interaction profiles.