CNP-miR146a Promotes NRF2-Related Ferroptosis-Protective Myeloid Programs and Immune-Vascular Regeneration in Diabetic Wounds.

Background: Diabetic wounds are characterized by chronic inflammation, oxidative stress, impaired angiogenesis, and delayed tissue repair. Ferroptosis has emerged as a potential contributor to diabetic wound pathology; however, its relationship with impaired tissue regeneration remains incompletely understood. Objectives: We investigated cellular and transcriptional responses associated with cerium oxide nanoparticle-conjugated microRNA-146a (CNP-miR146a) treatment and whether wound repair is associated with ferroptosis-protective programs and immune-vascular communication. Methods: Diabetic excisional wounds were treated with CNP-miR146a or phosphate-buffered saline controls. Single-cell RNA sequencing was performed on wound tissues, with primary analyses focused on postoperative Day 7. Cellular composition, ferroptosis-associated programs, pseudotime trajectories, and inferred ligand-receptor communication networks were analyzed. Results: CNP-miR146a treatment was associated with transcriptional remodeling of the diabetic wound microenvironment, with myeloid cells exhibiting a prominent response. Treatment was associated with higher NRF2-related antioxidant, ferroptosis-protective, and iron-homeostasis transcriptional programs and with a repair-associated myeloid state. Pseudotime analysis identified a trajectory from monocytes toward pro-regenerative macrophages accompanied by dynamic expression of antioxidant, iron-homeostasis, and repair-associated genes. CellChat predicted increased immune-vascular communication through angiogenic and extracellular matrix-associated pathways. Endothelial cells exhibited increased NRF2-associated transcriptional programs, angiogenesis-associated gene expression, and endothelial repair markers. Conclusions: CNP-miR146a-mediated wound repair is associated with coordinated ferroptosis-protective and NRF2-related transcriptional programs, pro-regenerative myeloid states, endothelial angiogenesis-associated programs, and predicted immune-vascular communication. These findings identify ferroptosis-associated and immune-vascular transcriptional networks as candidate mechanisms of CNP-miR146a-mediated diabetic wound repair requiring further functional validation.