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Oxygen-Tolerant Hydrogenase-Ag Nanoclusters-Peptide Hydrogel for Light-Driven H₂ Therapy in Diabetic Wound Healing

ABSTRACT: Diabetic wound healing is hindered by excessive reactive oxygen species (ROS), while conventional hydrogen (H₂) delivery methods lack localized efficacy. Escherichia coli [NiFe]-hydrogenase 2 (Hyd-2), though promising for H₂ production, suffers from oxygen sensitivity. Here, we engineer a peptide hydrogel (Fmoc-KYF-AgNCs) that shields Hyd-2 from oxygen inactivation, enabling sustained light-driven H₂ generation under aerobic conditions (retaining 80% activity after 12 hours). In vitro, the hydrogel scavenges ROS in LPS-stimulated macrophages, suppresses pro-inflammatory cytokines, and enhances cell survival. In diabetic mice, the hydrogel accelerates wound closure (87% by day 11), reduces oxidative stress, promotes angiogenesis, and reprograms macrophages toward an anti-inflammatory M2 phenotype. Transcriptomic profiling reveals downregulation of inflammatory pathways and upregulation of tissue repair genes. This oxygen-tolerant system bridges enzymatic catalysis with precision medicine, offering a translatable platform for diabetic wound therapy and expanding hydrogenase applications in oxidative stress-related disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE297828 | GEO | 2026/05/21

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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Oxygen-Tolerant Hydrogenase-Ag Nanoclusters-Peptide Hydrogel for Light-Driven H₂ Therapy in Diabetic Wound Healing

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