Neuropeptides as neuroimmune modulators in chronic wound healing: mechanistic insights and emerging therapeutic strategies

Chronic wounds, typified by diabetic foot ulcers, pressure ulcers, and venous leg ulcers, represent a major clinical challenge worldwide. Persistent inflammation associated with disrupted neuroimmune crosstalk is increasingly recognized as an important contributor to impaired chronic wound healing. Neuropeptides, including substance P, calcitonin gene-related peptide, neuropeptide Y, and vasoactive intestinal peptide, act as context-dependent neuroimmune mediators that regulate immune-cell states, inflammation resolution, angiogenesis, re-epithelialization, and extracellular-matrix remodeling through partly distinct mechanisms. This review systematically examines the molecular and cellular mechanisms through which these neuropeptides influence the chronic wound microenvironment, with particular attention to their dose-, phase-, receptor-, and cell-dependent effects. Emerging therapeutic strategies are also summarized, including conventional and stimuli-responsive hydrogels, nanoparticle–hydrogel composites, hydrogel microspheres, microneedles, electrospun scaffolds, cell-based approaches, extracellular-vesicle-based combination strategies, electrical stimulation, photobiomodulation, and anti-infective combination platforms. Most of the available evidence remains preclinical. Key translational challenges include peptide instability, receptor desensitization, wound heterogeneity, delivery-system manufacturing and standardization, and peptide-specific long-term safety. Collectively, current evidence supports neuropeptide signaling as a promising but context-dependent target for precision neuroimmune modulation in chronic wound healing.