LysSYL‐Loaded pH‐Switchable Self‐Assembling Peptide Hydrogels Promote Methicillin‐Resistant Staphylococcus Aureus Elimination and Wound Healing

Abstract Staphylococcus aureus ( S. aureus ), especially methicillin‐resistant S. aureus (MRSA), causes wound infections, whose treatment remains a clinical challenge. Bacterium‐infected wounds often create acidic niches with a pH 4.5–6.5. Endolysin LysSYL, which is derived from phage SYL, shows promise as an antistaphylococcal agent. However, endolysins generally exhibit instability and possess low bioavailability in acidic microenvironments. Here, an array of self‐assembling peptides is designed, and peptide L5 is screened out based on its gel formation property and bioavailability. L5 exerted a pH‐switchable antimicrobial effect (pH 5.5) and formed biocompatible hydrogels at neutral pH (pH 7.4). The LysSYL‐loaded L5 can assemble L5@LysSYL hydrogels, increase thermal stability, and exhibit the slow‐release effect of LysSYL. Effective elimination of S. aureus is achieved by L5@LysSYL through bacterial membrane disruption and cell separation inhibition. Moreover, L5@LysSYL hydrogels exhibit great potential in promoting wound healing in a mouse wound model infected by MRSA. Furthermore, L5@LysSYL hydrogels are safe and can decrease the cytokine levels and increase the number of key factors for vessel formation, which contribute to wound healing. Overall, the self‐assembling L5@LysSYL can effectively clean MRSA and promote wound healing, which suggests its potential as a pH‐sensitive wound dressing for the management of wound infections.