Exosome-microneedle patches accelerate oral ulcer healing by remodeling macrophage-epithelial crosstalk via TSP‑1/CD47/NF‑κB signaling

Oral ulcers are among the most common inflammatory lesions of the oral mucosa and often cause severe pain. However, current treatments are limited by short mucosal retention, suboptimal therapeutic efficacy, and steroid-associated side effects, underscoring the need for more effective and durable therapeutic strategies. Here, we developed exosome-loaded microneedle patches (Exo-MNPs) by incorporating mesenchymal stem cell-derived exosomes (MSC-exo) into gelatin methacryloyl (GelMA)/polyvinylpyrrolidone (PVP) microneedles and evaluated their potential to accelerate oral ulcer healing. Exo-MNPs were systematically characterized in terms of morphology, mechanical strength, and in vitro bioactivity. In rat ulcer models, Exo-MNPs markedly accelerated wound closure, promoted epithelial regeneration, reduced inflammation, and increased collagen deposition. Multi-omics profiling using single-cell RNA sequencing (scRNA-seq) and proteomics revealed that Exo-MNPs act through the TSP-1/CD47/NF-κB axis to reprogram macrophage phenotypes and promote regenerative epithelial subpopulations via intercellular crosstalk. These findings demonstrate that Exo-MNPs represent a promising localized bioactive therapy for oral ulcers and illuminate key immune–epithelial mechanisms underlying their therapeutic effects. • Exosome-loaded microneedles accelerate oral ulcer healing through efficient local delivery in oral mucosa. • ScRNA-seq and exosome proteomics identify TSP−1 as a key effector in mucosal repair. • Exosomal TSP−1 suppresses NF-κB signaling and reshapes macrophage–epithelial crosstalk during repair.