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

ABSTRACT: 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.

ORGANISM(S): Rattus norvegicus Homo sapiens

PROVIDER: GSE308113 | GEO | 2025/10/17

REPOSITORIES: GEO

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Project description:Diabetic wounds require continuous and coordinated modulation of the microenvironment concurrent with tissue regeneration, yet this remains a significant challenge. As a proof of concept, we herein propose to use dimeric copper peptide for diabetic wound treatment. The dimeric copper peptide (D-CuP) was first synthesized and then incorporated into a reactive oxygen species (ROS)-responsive hydrogel matrix to improve therapeutic compliance, culminating in the formulation of G/D-CuP. Compared to monomer copper peptide (CuP), a wound healing agent, D-CuP exhibits multivalency, enhanced biologic stability against proteases and the broad biological activities, such as anti-inflammatory and antioxidative properties, while promoting angiogenesis and fibroblast proliferation and migration. Meanwhile, the hydrogel matrix, exhibiting excellent ROS-scavenging capabilities, has been engineered to an intelligent drug reservoir for wound-responsive release of D-CuP at the wound site while simultaneously attenuating inflammatory responses. Ultimately, the G/D-CuP group demonstrated superior therapeutic efficacy, achieving in 97.2% closure of infected wounds.In this study, we present a proof-of-concept study to optimize the treatment of diabetic wounds. This method integrates a dimeric copper peptide hydrogel (G/D-CuP) to address several critical factors: i) The design and synthesis of the dimeric copper peptide (D-CuP) feature a broad range of targets and enhanced biological activities, such as anti-inflammatory and antioxidative properties, while promoting angiogenesis and fibroblast proliferation and migration; ii) Utilizing the steric hindrance conferred by dimerization reduces protease access to the active site and significantly improving stability against proteases; iii) A ROS-responsive hydrogel matrix has been synthesized, exhibiting superior ROS-scavenging capabilities, functioning as an intelligent drug reservoir that enables the controlled release of D-CuP at the wound interface while simultaneously attenuating inflammatory responses in the microenvironment; iv) G/D-CuP possesses outstanding deformability and spreadability, allowing it to adapt to any wound shape; v) The synthesis and preparation process of G/D-CuP are straightforward and cost-effective, making it highly promising for clinical translation. This multifunctional treatment platform is anticipated to accommodate the complex and dynamic biological processes involved in diabetic wound healing, thereby significantly improving the overall efficacy of wound healing treatments.

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

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