Reversing diabetic wound stagnation: macrophage polarization dysregulation as a therapeutic linchpin from pathogenesis to precision interventions

The stagnation of diabetic wound healing is a formidable global health challenge that is fundamentally driven by the dysregulation of macrophage plasticity. In the diabetic microenvironment, macrophages remain in a persistent pro-inflammatory (M1) state and fail to transition to the reparative (M2) phenotype essential for tissue regeneration. This review systematically elucidates the molecular pathology of this ‘conversion failure’ from a superficial to an in-depth level and provides a detailed explanation of the mechanisms underlying aberrant macrophage polarization in diabetic wounds, ranging from microenvironmental abnormalities to dysregulated signalling pathways. These perturbations create a vicious cycle of chronic inflammation, impaired angiogenesis, and pathological fibrosis. To address these challenges, we comprehensively outline current therapeutic strategies, including approaches that range from the precision molecular reprogramming of intracellular signalling hubs and gene networks to the engineering of microenvironment-responsive biomaterials capable of neutralizing oxidative stress and responding to pathological cues. Furthermore, we highlight the integration of exogenous bioactivity through stem cell– and exosome-based therapies aimed at replenishing the regenerative niche. Additionally, we critically assess translational bottlenecks, suggesting a paradigm shift from the binary M1/M2 model towards targeting intermediate phenotypes identified by single-cell multiomics. By integrating mechanistic insights with advanced immunomodulatory engineering, this review provides a theoretical framework for developing next-generation precision therapies to reverse the chronic nature of diabetic wounds.