Nanoparticle-driven macrophage polarization as a therapeutic strategy for chronic diabetic wounds

Chronic diabetic wounds, including diabetic foot ulcers, present significant clinical challenges due to persistent inflammation, oxidative stress, impaired angiogenesis, infection, and defective tissue regeneration. Central to these pathological features is macrophage dysfunction, wherein immune cells become locked in a pro-inflammatory state that impedes the transition to reparative phenotypes necessary for resolution of inflammation and tissue repair. Nanomedicine-based strategies have emerged as promising approaches to restore macrophage plasticity and promote regenerative healing. Multifunctional nanotherapeutic platforms including antioxidant nanozymes, extracellular vesicle- and exosome-based delivery systems, oxygen-generating and gasotransmitter-releasing materials, infection-controlling nanoparticles, plant-derived bioactive nanomedicines, and advanced hydrogel or scaffold-based carriers have demonstrated the ability to modulate oxidative stress, mitochondrial function, inflammasome activation, immunometabolism, efferocytosis, and intercellular communication. By reprogramming macrophages toward pro-regenerative states, these interventions facilitate angiogenesis, extracellular matrix remodeling, and epithelial restoration, effectively converting a hostile wound microenvironment into a tissue-repair permissive niche. This review highlights recent advances in nanoparticle-driven macrophage polarization for diabetic wound healing, detailing the molecular mechanisms, therapeutic platforms, and regenerative outcomes, while also discussing translational challenges including biological complexity, biosafety, manufacturing, and preclinical model limitations. Future perspectives emphasize precision immunomodulation, biomarker-guided patient stratification, and clinically translatable nanomedicine strategies to optimize chronic wound repair.