Macrophage Dynamics in Diabetic Wounds: Mechanisms, Signalling Pathways, and Therapeutic Innovations.

Abstract

Diabetic wounds are among the most challenging complications of diabetes mellitus, and approximately one in four patients with diabetes is expected to develop such a wound during their lifetime. The majority of diabetes-related amputations are attributable to complications of diabetic wounds. In conditions characterized by impaired wound healing, macrophage polarization is dysregulated, primarily due to the persistence of M1 macrophages and a delayed switch to the reparative M2 phenotype. This article reviews the molecular, signalling, and epigenetic mechanisms that regulate macrophage function in diabetic wound healing. The key signalling pathways PI3K/AKT, NF-κB, and Notch play essential roles in determining the balance between inflammatory and reparative processes, whereas DNA methyltransferases, histone-modifying enzymes, and non-coding RNAs control the transcriptional programs that drive macrophages toward either the M1 inflammatory or the M2 reparative phenotype. This review examines how emodin and Astragalus Polysaccharides (APS) modulate these mechanisms to promote M2 polarization and reduce oxidative stress in diabetic wounds. Immunomodulatory hydrogels, extracellular vesicles, and genetargeted nanoparticles can deliver this reprogramming potential directly to the wound site; however, clinical translation remains difficult because macrophage phenotype shifts unpredictably in the in vivo wound environment, and no current platform achieves reliable targeted delivery to wound macrophages. Future research should combine such delivery vehicles with epigenetic and gene-editing tools to restore immune equilibrium and tissue regeneration. Ultimately, modulation of macrophage plasticity may enhance diabetic wound healing and reduce the global burden of chronic non-healing ulcers.