# RNA modifications: molecular orchestrators of wound healing

## TL;DR

This review explores how RNA modifications influence wound healing, especially in burns and trauma, and identifies potential therapies like hydrogels and nanoparticles.

## Contribution

The paper integrates RNA modification mechanisms with wound healing phases and proposes translational strategies for burns and trauma.

## Key findings

- RNA modifications regulate macrophage polarization and stem cell fate during wound healing.
- N6-methyladenosine and other RNA modifications play key roles in tissue regeneration and inflammation.
- Therapeutic strategies like exosome-based therapies and bone-targeted nanoparticles show promise for clinical translation.

## Abstract

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: N6-methyladenosine, 5-methylcytosine, N7-methylguanosine, and N4-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.

Graphical Abstract

Figure created with BioRender.com (license: CP296TZDNK).