Direct Protein–Polymer Conjugation via Tyrosine-Terminated Radical Polymerization

Protein–polymer conjugates (PPCs) combine the unique bioactivities of the proteins with the tunable properties of the polymers, but their synthesis typically requires premodification of components. Herein, we report the occurrence of radical polymerization termination by phenol derivatives as a prevalent side reaction, allowing direct covalent conjugation of polymer chains to solvent-accessible tyrosine residues in native proteins. This reaction, we termed grafting via tyrosine-terminated radical polymerization (TyrTer-grafting). TyrTer-grafting exhibits applicability to diverse monomers and proteins, achieves improved conjugation efficiency under proximity-driven enzymatic catalysis, and preserves protein function more effectively than the traditional activated ester-mediated method. In addition, TyrTer-grafting enables both direct cell-surface polymerization to control cellular aggregation and anchor-free expansion microscopy (ExM) to generate high-quality images with super-resolved details. This work provides a new perspective for fabricating functional macromolecules and presents a significant discovery for radical chemistry and bioconjugation chemistry.