RNA modifications: molecular orchestrators of wound healing

Wound healing is a highly coordinated biological process traditionally divided into three phases: inflammatory, proliferative, and remodeling. Diabetes and acute trauma markedly disrupt these stages, resulting in delayed wound closure, persistent inflammation, and impaired tissue regeneration. This review focuses on three trauma-relevant contexts: (i) skin wounds, including diabetic ulcers and burns; (ii) bone fracture healing; and (iii) corneal epithelial and stromal injury. Robust in vivo evidence is synthesized to delineate the mechanistic roles of the four principal ribonucleic acid (RNA) modifications: N ⁶-methyladenosine, 5-methylcytosine, N ⁷-methylguanosine, and N ⁴-acetylcytidine. Additionally, the roles of RNA modification writers, erasers, and readers in regulating macrophage polarization, stem and progenitor cell fate, angiogenesis, lymphangiogenesis, and extracellular matrix remodeling are examined. Evidence across different tissues and wound healing phases is integrated rather than presented descriptively. Methodological limitations are highlighted, and knowledge gaps are identified alongside testable hypotheses. Translational opportunities with direct relevance to burn and trauma management are emphasized. This review aims to integrate mechanistic and translational insights into a coherent framework for therapeutic intervention. By defining how RNA modifications intersect with distinct wound healing phases, concrete therapeutic entry points and delivery strategies relevant to burns and trauma are identified, including topical hydrogels, exosome-based therapies, and bone-targeted nanoparticles. Designs for pragmatic clinical trials and biomarker strategies that enable translation of preclinical findings to patients are also discussed.