Polymerization-Induced Chiral Supramolecular Polypeptide Hydrogels for Enhanced Mechanical Property and Selective Bioactivity

Fibrous chiral hydrogels capable of mimicking extracellular matrix (ECM) architectures are of significant interest in biomaterial research. Here, we report the first use of a one-pot polymerization-induced self-assembly (PISA) strategy to construct injectable polypeptide hydrogels with superhelical fibers. By tuning the amphiphilic balance and secondary structures in poly(ethylene glycol)-block-poly(L/D-glutamate)s with tailored hydrophobic side groups, β-sheet formation is promoted, driving assembly into supramolecular superhelices at a concentration of 6 wt %, exhibiting storage moduli up to 3.7 kPa─an order of magnitude higher than those of conventional spherical micellar poly(ethylene glycol)-polypeptide hydrogels. The handedness of the assemblies is governed by the chirality of the L- and D-enantiomers, whereas racemic polymerization yields stereoenriched hydrogels rather than nongelling atactic analogues. Left-handed superhelical hydrogels exhibit superior protein adsorption, cell adhesion and proliferation, and immune activation. In contrast, their L- and D-spherical micellar counterparts display lower activity with a negligible difference. Moreover, stereoenriched hydrogels outperform physical mixtures of L- and D-polypeptide stereocomplexes. We demonstrate that supramolecular topology, rather than molecular chirality alone, is the key determinant of bioactivity and immune recognition, establishing a robust and scalable platform for engineering ECM-like hydrogels for biomedical applications.