Investigating FTY720-NF immunomodulation of key lipid, gene, and protein mediators to enhance oral tissue regeneration.

Oronasal fistula (ONF) formation following cleft palate repair remains a significant clinical challenge, often driven by persistent inflammation, fibrotic remodeling, and insufficient mucosal regeneration. Effective oral wound healing depends on precise immune regulation, particularly by macrophages that coordinate both inflammation resolution and tissue repair. The sphingosine-1-phosphate (S1P) pathway is a key regulator of immune cell function and trafficking, and its modulation through the S1P receptor agonist FTY720 (Fingolimod) offers a promising multifaceted strategy for tissue regeneration. In this study, we investigated the therapeutic effect of FTY720 delivered via nanofibers (FTY720-NF) on macrophage-mediated wound repair using multi-omics profiling and translational in vivo models. Treatment of human macrophages with phosphorylated FTY720 (FTY720P) in vitro induced a shift in cytokine and chemokine secretion toward a pro-regenerative phenotype. Integrated lipidomic and transcriptomic analyses revealed significant remodeling of sphingolipid metabolism and gene expression networks associated with pro-regenerative macrophage phenotypes and inflammation resolution. In a porcine model of oral injury, FTY720-NF treatment accelerated re-epithelialization and improved wound healing outcomes compared to injury-only and platelet-rich plasma (PRP) controls. Together, these findings highlight FTY720-NF as a potential immunotherapeutic approach that possibly reprograms cellular responses and tissue environments to promote oral wound healing.