Star-Shaped Polyphenolic Polypeptides Serving as Assembling-Typed Drug Carriers

Star polypeptides are the next frontier of biomedical materials owing to their unique physicochemical properties, whereas their translation is challenged by the strict criteria of biomedical materials in synthesis efficiency, structure determinacy, and biological safety. Herein, we develop a 1,1,3,3-tetramethylguanidine (TMG)-catalyzed, multiple oxhydryl-initiated <i>N</i>-carboxyanhydride (NCA) ring-opening polymerization strategy, synthesizing a series of star polypeptides with tannic acid (TA) cores and polymeric arms. Harnessing TMG's catalytic functions in enhancing oxhydryl nucleophilicity for TA and activating the reaction center for NCA monomers, our strategy achieves efficient polymerization with monomer conversion reaching 91.6%. The obtained polyphenolic polypeptides expand TA's radiative architecture, exhibiting a star topology with well-defined arm numbers and lengths. Integrating TA's metal coordination potentials with polypeptides' self-assembly functionalities, these star polyphenolic polypeptides show remarkable nanofabrication capacities, achieving broad-spectrum small-molecule drug encapsulation. Additionally, exploiting natural TA as a multisite initiator for NCA polymerization fundamentally improves the biosafety of polypeptides, thus facilitating biomedical applications.