Restoring the repair–fibrosis balance via a localized extracellular vesicle–pirfenidone dual-delivery biomaterial platform promotes ureteral repair after thermal injury

INTRODUCTION: Ureteral thermal injury can lead to ureteral stricture through persistent oxidative stress, inflammation, impaired vascular repair, and excessive fibrosis. Current treatment strategies primarily aim to restore urinary drainage or address established structural obstruction, whereas approaches that simultaneously modulate tissue repair and postinjury fibrotic remodeling remain limited. OBJECTIVES: This study aimed to develop a localized dual-delivery biomaterial platform that simultaneously promotes tissue repair and suppresses excessive fibrosis after ureteral thermal injury. METHODS: A localized EG_PFM platform was fabricated by combining a mesenchymal stem cell-derived extracellular vesicle (MSC-EV)-loaded chitosan/hyaluronic acid hydrogel (EG) with a pirfenidone (PF)-loaded poly(lactic-co-glycolic acid) nanofibrous membrane (PFM). The physicochemical properties and release profiles were characterized. In vitro, the effects of MSC-EVs and PF on urothelial and smooth muscle cell relative cell growth and migration, oxidative stress, angiogenesis, macrophage phenotype, and fibrosis-associated cellular responses were evaluated. A rabbit model of ureteral thermal injury was established to assess ureteral structural repair, hydronephrosis, collagen deposition, oxidative stress, inflammation, angiogenesis, and transcriptomic changes. RESULTS: EG_PFM exhibited favorable biocompatibility, tissue adhesion, and sustained release of MSC-EVs and PF. MSC-EVs increased relative cell growth and enhanced the migration of urothelial and smooth muscle cells, reduced intracellular reactive oxygen species, enhanced endothelial tube formation and were associated with an M2-like macrophage phenotype, whereas PF suppressed α-SMA expression and extracellular matrix accumulation. In rabbits, EG_PFM reduced hydronephrosis and ureteral stricture, decreased collagen deposition, oxidative stress, and inflammatory responses, and enhanced vascularization. Transcriptomic analysis identified treatment-associated changes in multiple signaling and metabolic pathways, including calcium signaling, cell adhesion molecules, tyrosine metabolism, and retinol metabolism. CONCLUSION: Localized codelivery of MSC-EVs and PF promoted reparative responses while limiting fibrotic remodeling, thereby improving structural repair after ureteral thermal injury. EG_PFM represents a promising localized therapeutic strategy for reducing postinjury ureteral stricture.