Immunometabolic reprogramming of macrophages by miR-423-5p-enriched small extracellular vesicles delivered via glucose/ROS-responsive hydrogel for diabetic wound healing.

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

Chronic diabetic wounds remain a formidable clinical challenge due to a self-sustaining immunometabolic dysfunction. The hyperglycemic and pro-oxidative microenvironment locks infiltrating macrophages in a glycolysis-dependent pro-inflammatory state, actively suppressing the phenotypic switch to pro-reparative M2 polarization and severely impairing angiogenesis. Current single-target interventions fail to disrupt this vicious inflammatory-metabolic cycle, underscoring an urgent need for strategies capable of spatiotemporally resetting local immune homeostasis. In this study, the pro-reparative capacity of ADSCs-EVs and UCMSCs-EVs was systematically compared through a panel of in vitro functional assays (proliferation, migration, tube formation, and macrophage polarization) and a diabetic mouse wound model. Small RNA sequencing was employed to identify a key effector miRNA enriched in UCMSCs-EVs, and its target regulatory mechanism was validated through miRNA mimic transfection combined with HDDC3 overexpression rescue experiments. Meanwhile, a glucose/ROS dual-responsive injectable hydrogel (DCH) was constructed from oxidized dextran, carboxymethyl chitosan, and phenylboronic acid-modified hyaluronic acid via physical mixing and dynamic double crosslinking through Schiff-base and boronate ester bonds, enabling the pathology-triggered, on-demand release of EVs. Comparative bioac

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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