Nervous System Repair and Immunity: Chiral Effects of Biomimetic Self‐Assembled Neuropeptide Hydrogels

Abstract Function‐encoding peptides have emerged as promising biomaterials capable of replicating the robust biological functions of the extracellular matrix (ECM). Nevertheless, the full potential of their sequence designability remains to be explored to develop highly bioactive peptide‐based biomaterials with minimal immunogenicity. In this study, chiral peptides are self‐assembled into supramolecular hydrogels (FFFKTTKS/fffkttks) incorporating an active sequence derived from collagen hydrolysis, a key ECM factor. While FFFKTTKS (L‐type) and fffkttks (D‐type) peptide‐based hydrogels exhibit comparable viscoelasticity, porosity, and supramolecular architecture, they differ in their nanofiber composition, particularly in helical orientation. In a model of spinal cord injury, the FFFKTTKS hydrogel demonstrates superior neuronal regeneration and motor function recovery compared to its fffkttks counterpart. Further investigations reveal that both FFFKTTKS and fffkttks hydrogels equally promote the expression of ECM‐related genes, subsequently regulating nerve cell adhesion, neuronal differentiation, and synaptic regeneration. Notably, the FFFKTTKS hydrogel elicits a mild immune response and exhibits moderate anti‐inflammatory properties. In contrast, the fffkttks hydrogel triggers a robust immune response, activating the TNF pathway in microglia in vivo. These findings underscore that nanoscale chiral superstructures of specific peptide sequences can effectively modulate biocapability and neuroregeneration, providing critical insights for the rational design of peptide‐based synthetic ECM.