Integrative neuromodulation in diabetic foot infections: electroacupuncture-driven macrophage reprogramming and...

Diabetic foot infections (DFIs) are characterized by persistent bacterial biofilms and impaired host immune defenses. Within the diabetic microenvironment, peripheral neuropathy disrupts neuro-immune feedback loops, contributing to the arrest of resident macrophages in a pro-inflammatory M1 phenotype. This phenotypic arrest impairs efferocytosis and sustains chronic inflammation, which conventional antimicrobial therapies frequently fail to resolve. Electroacupuncture (EA) serves as a neuromodulatory intervention capable of reversing this immune dysfunction. By stimulating specific somato-autonomic reflexes-including the vagal-adrenal and sympathoadrenal axes-EA activates the systemic cholinergic anti-inflammatory pathway (CAP). The subsequent release of neurotransmitters, acting on receptors such as the α7 nicotinic acetylcholine receptor (α7nAChR) on macrophages, inhibits pro-inflammatory cascades and promotes polarization toward the pro-repair M2 phenotype. Concurrently, EA-induced localized neuropeptide release and vasodilation mitigate the ischemic microenvironment, providing metabolic support for sustained pathogen clearance. Furthermore, this review proposes a translational "Vanguard and Commander" approach, integrating the localized biofilm-disrupting properties of advanced antimicrobial biomaterials (the "vanguard") with the sustained immune reprogramming mediated by EA (the "commander"). This integration links material science with bioelectronic neuromodulation to coordinate the tissue repair process spatiotemporally. Ultimately, this combined approach provides an opioid-sparing, integrative therapeutic strategy for the management of refractory diabetic wound infections.