Chirality in hydrogels assembled from D- or L-amino acid derivatives regulates immunological responses during...

Immunomodulatory biomaterials that perform specific host immune responses have shown great prospects for immunotherapies and regenerative medicine. Although there is a growing recognition of chirality in manipulating cell behavior, the regulatory role of matrix chirality on immune cell function and heterogeneity is still not well understood. Herein, we develop a three-dimensional artificial fibrotic extracellular matrix (ECM) from supramolecular chiral hydrogels assembled from either D- or L-amino acid derivatives and investigate how chirality regulates immunological response during diabetic wound healing processes. By providing a chiral supramolecular microenvironment, the supramolecular hydrogels enable the ECM to be preprogrammed toward an M2 phenotype via chirality-dependent extracellular internalization, thereby establishing an immune milieu favorable for tissue repair and further regulating fibroblast functions. Mechanistically, matrix chirality provides a stereochemical cue that can bias macrophage polarization and immune heterogeneity by modulating cell-matrix recognition, extracellular uptake/internalization, and the hierarchical organization of downstream signaling events. Murine diabetic ulcer models show that supramolecular right-handed hydrogels activate specific immune responses and improve the quality of wound healing. Furthermore, molecular analysis provides evidence that right-handed chirality of the ECM benefits the clustering of multiple wound healing-related signaling pathways into coordinated networks, i.e., PI3K-Akt with the highest possibility, while left-handed chirality downregulates this effect. Such chirality-guided pathway clustering establishes a mechanistic link between ECM stereochemistry and macrophage-state distributions, thereby enabling fine regulation of immune heterogeneity in vivo. These findings offer insights into how supramolecular hydrogels may be engineered as drug delivery matrices that integrate stereochemical cues with controlled immunomodulation, ultimately improving therapeutic outcome.