Film-forming sprays for wound healing: A critical review of iron chelator–antibiotic combination strategies

Background and objective Wound healing is a complex, multifactorial process frequently compromised by microbial infection, biofilm formation, and dysregulated oxidative stress. Conventional dressings fail to provide sustained drug delivery, effective barrier function, and localized antimicrobial activity. Film-forming sprays (FFS) have emerged as promising topical delivery systems that generate in situ polymeric films enabling controlled drug release, mechanical protection, and improved patient compliance. This review uniquely evaluates the rational combination of antibiotics including mupirocin, fusidic acid, gentamicin, and clindamycin with repurposed iron chelators deferoxamine (DFO), deferiprone (DFP), and deferasirox (DFX) within FFS platforms. It critically appraises their mechanistic synergy, formulation challenges, translational gaps, and safety considerations. This is the first review to comprehensively address this combination within the FFS context. Methods A structured literature search was performed across PubMed, Scopus, and Web of Science (January 2000–March 2025) using Boolean combinations of predefined keywords. Studies were screened by two independent reviewers against pre-specified inclusion and exclusion criteria. Results Iron chelation disrupts bacterial iron acquisition via siderophore competition, reduces reactive oxygen species (ROS)-mediated tissue injury, impairs biofilm extracellular matrix stability, and activates hypoxia-inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF) pathways to promote angiogenesis. These effects synergistically enhance the efficacy of co-administered antibiotics. Mupirocin and fusidic acid are identified as preferred antibiotics due to their absence of metal-binding functional groups. Tetracyclines and fluoroquinolones must be avoided due to iron-complex formation. Twelve formulation-specific challenges with evidence-based solutions are critically appraised. No published study has yet combined an iron chelator with an antibiotic within a single FFS platform this constitutes the most critical gap identified. Conclusion Iron chelator–antibiotic FFS represent a mechanistically rational, dual-functional wound care strategy. However, direct clinical evidence is absent. Systematic formulation development, in vivo validation in diabetic and biofilm-infected wound models, and dedicated safety and regulatory studies are required before clinical translation.