Background and objectives:Exosomes therapy is a promising technique that can decrease the concern related to the fate of transplanted stem cells to the fistula location. The unique properties of mesenchymal stem cells (MSCs)-derived exosomes can improve fistula healing because of their high ability to regulate and modify immune responses. This project aims to examine the safety and efficacy of implementing MSCs-exosomes in treating refractory fistulas in inflammatory bowel disease (IBD) patients.Methods:The exosomes were isolated from umbilical cord-derived MSCs and characterized using flow cytometry, western blotting, and transmittance electron microscope (TEM). Five patients (three men and two women) with refractory perianal Crohn's disease with an average age of 35.4 years old were included. The patients did not match the exclusion criteria, and the presence of refractory fistulas was the main inclusion criteria. These patients have their exosomes injections in the operation room. The therapy responses of patients were assessed using physical examination, face-to-face interviews, computerized tomography (CT) scan, and magnetic resonance imaging (MRI) six months later.Result:The Following injection, patients reported a 70% improvement on average. Two patients claimed complete healing after exosome injections, while one patient reported no improvement and active discharge from the fistula site. In addition, five patients reported no adverse effects, both systemic or on the injection site.Conclusion: Injection of exosomes extracted from MSCs shows total safety and a satisfactory therapeutic impact, as shown in this and other research, and could play a significant role in the treatment of gastrointestinal fistulas in the future.