L-Chiral Hydrogel Accelerates Wound Healing via Lactate-Mediated RNF123 K57 Lactylation

Chronic wounds, characterized by delayed healing and persistent inflammation, represent a major clinical burden with limited effective therapies. Inspired by the stereoselective interactions in biological systems, we developed an L-chiral hydrogel composed of self-assembled helical nanofibers from L-histidine derivatives, which preferentially enriches lactate to promote wound repair. Compared to D-chiral and racemic hydrogels, the L-chiral hydrogel significantly accelerated wound closure in rat models, achieving nearly 90% healing by day 14 and reducing healing time to 16-17 days. Transcriptomic and metabolomic analyses revealed enhanced wound response pathways and elevated lactate levels in the L-chiral group. Mechanistically, enriched lactate induced K57 lactylation of RNF123, mediated by AARS1, altering RNF123 conformation and weakening its binding to UBAC1. This modification enhanced ubiquitination and processing of NF-κB p105 into p50, inhibiting the NF-κB pathway and promoting angiogenesis via enhanced endothelial cell migration, tube formation, and sprouting. Rescue experiments with lactate inhibitor Oxamate and exogenous lactate confirmed the lactate-dependent mechanism. This study not only demonstrates a drug-free chiral biomaterial for efficient wound healing but also unveils the molecular role of lactate-mediated lactylation in mechanoregulating inflammation and vascularization, offering new insights for regenerative medicine.