Bifunctional Artificial Enzymes-Loaded Microgels With LOX- and CAT-Like Activities for Metabolic Reprogramming and...

Area of Science:

• Biomaterials Science
• Regenerative Medicine
• Biochemistry

Background:

• Lactate accumulation in wounds drives fibrosis via histone lactylation and endothelial-to-mesenchymal transition.
• Limited strategies exist to address lactate-driven metabolic imbalance and oxidative stress in wound healing.
• Targeting metabolic dysregulation is crucial for promoting scarless skin regeneration.

Purpose of the Study:

• To develop a novel artificial enzyme system, Metazyme, with dual lactate oxidase (LOX)-like and catalase (CAT)-like activities.
• To create a localized and sustained catalytic platform, MetaRgel, for wound microenvironment modulation.
• To investigate the efficacy of MetaRgel in reducing inflammation, oxidative stress, and fibrosis while promoting wound healing.

Main Methods:

• Development of Metazyme with LOX and CAT activities for lactate oxidation and hydrogen peroxide decomposition.
• Embedding Metazyme into a rod-shaped microgel matrix to form MetaRgel for localized delivery.
• In vitro assessment of MetaRgel's effects on lactate, reactive oxygen species (ROS), glycolysis-related enzymes (PKM2, PDK1), interleukin-6 (IL-6), and transforming growth factor-β1 (TGF-β1).
• In vivo evaluation of MetaRgel in a rat full-thickness wound model, assessing healing, granulation, collagen organization, and fibrotic markers (α-SMA, HIF-1α).

Main Results:

• MetaRgel effectively reduced lactate and ROS levels, relieved hypoxia, and downregulated glycolysis-related enzymes in vitro.
• In vitro studies showed suppression of pro-inflammatory cytokine IL-6 and fibrotic mediator TGF-β1.
• In vivo, MetaRgel significantly accelerated wound healing, enhanced granulation and collagen organization.
• Significant reduction in glycolytic enzyme activity, α-smooth muscle actin (α-SMA), and hypoxia-inducible factor 1α (HIF-1α) was observed in vivo.

Conclusions:

• Targeting lactate-centered metabolic dysregulation with cascade artificial enzymes offers a promising therapeutic strategy.
• MetaRgel effectively modulates the wound microenvironment by addressing inflammation, metabolism, and oxidative stress.
• This approach holds potential for interrupting inflammation-metabolism-fibrosis crosstalk and promoting scarless skin regeneration.