Bioactive Hydrogels with D‐Amino Acid RGD Mimics: A Therapeutic Strategy for Expeditious Infected Wound Closure

Developing biomaterials that simultaneously support tissue repair while inhibiting infection remains a critical challenge in wound-healing research. Here, a novel series of D-amino acid and D/L-hybrid analogs has been synthesized to investigate the influence of stereochemistry on wound healing and antimicrobial activity. Self-assembly into a nanofibrous network enables these peptides to form hydrogels that serve as injectable, biomimetic scaffolds for drug delivery and antimicrobials, making them ideal for advanced wound-healing applications. Molecular docking revealed the strongest binding affinity of AN2D3 peptide toward integrin αvβ3, suggesting it as a promising lead candidate for targeting αvβ3-mediated pathways in cell adhesion and proliferation. Further, these peptides are systematically evaluated in methicillin-resistant Staphylococcus aureus (MRSA)-infected Balb/c mice to assess their antimicrobial activity, mechanical integrity, and regenerative potential. Remarkably, as the D-amino acid content increased in the sequences, antimicrobial efficacy and wound-healing also improved. Among peptide sequences, AN2D3 yielded the best results, highlighting the critical role of stereochemistry in peptide-based constructs. These hydrogels were designed to resist enzymatic degradation while promoting interactions with the extracellular matrix and innate antimicrobial activity. This inversion of stereochemistry is anticipated to influence the bioactivity of the peptide hydrogels, suggesting that even subtle shifts in chirality may affect biomaterial behavior.