Efficient Dual Surface Modification of Cellulose Nanocrystals with Hydrophobic Moieties and Functional Polymers via a Grafting-to Approach.

Cellulose nanocrystals (CNCs) are promising nanomaterials for biomedical applications owing to their biocompatibility, low toxicity, and versatile surface chemistry. However, efficient surface modification of CNCs with hydrophobic moieties and functional polymers remains challenging under mild aqueous conditions. Herein, we present an aqueous-phase "grafting-to" strategy that enables orthogonal conjugation of meso-tetra(4-carboxyphenyl)porphine (TCPP) and polyethylene glycol (PEG)-based polymers using a heterobifunctional linker. Aldehyde-functionalized CNCs were modified with dibenzocyclooctyne (DBCO)-amine via reductive amination to introduce two key functionalities: a secondary amine for amide coupling and a strained alkyne for copper-free click chemistry. We hypothesize that the hydrophobic environment surrounding the DBCO-modified CNC surface facilitates the noncovalent association of hydrophobic TCPP molecules, thereby significantly enhancing the conjugation reaction in water via the hydrophobic effect. The resulting dual-functionalized CNCs exhibited >1 month colloidal stability in water, reduced nonspecific protein adsorption by over 86% after PEGylation, and presented a versatile platform for biological applications.