Gas therapeutics for wound healing: Therapeutic potential of oxygen and nitric oxide

Chronic wounds continue to pose a major clinical and socioeconomic challenge, affecting millions of patients worldwide. Their persistence is often driven by impaired oxygenation, persistent infection, biofilm formation, and dysregulated inflammation, all of which disrupt the normal healing cascade. In recent years, gas-based therapeutics particularly oxygen (O₂) and nitric oxide (NO) have attracted considerable attention for their multifaceted roles in tissue repair. Oxygen is essential for cellular metabolism, angiogenesis, and collagen deposition, whereas NO modulates vascular tone, coordinates immune responses, and provides potent antimicrobial activity. This review systematically examines the molecular mechanisms by which O₂ and NO individually and synergistically regulate all four phases of wound healing with particular emphasis on the signalling that link oxygen availability to NO biosynthesis. The challenges related to delivery, dosage, and stability persist. Importantly, a growing body of evidence highlights the biochemical interplay between O₂ and NO, where oxygen stabilizes NO synthesis, and NO mediates oxygen signalling pathways, particularly in angiogenesis and immune modulation. This interdependence suggests that combined O₂-NO delivery may offer superior therapeutic outcomes compared to single-gas approaches. Advances in biomaterials, nanotechnology, and smart dressing design now enable the development of dual-delivery systems capable of controlled and sustained release. Future work should focus on personalized wound care strategies, integration of dual gas therapies with conventional modalities, and large-scale clinical validation to translate biology into practice.