Therapeutic potential and mechanistic insights into adipose-derived stem cells and mesenchymal stem cell-derived exosomes in patients with Crohn's disease-associated fistulas: challenges and future perspectives.

Exosomes, as noninvasive biological carriers, have emerged as promising therapeutic agents for a wide range of diseases because of their ability to deliver bioactive molecules and modulate intercellular communication. Their interaction with stem cells (SCs), which naturally secrete regenerative factors, further enhances their therapeutic potential. In particular, the use of adipose-derived stem cells (ADSCs) and exosome-enriched mesenchymal stem cell (MSC) preparations has been explored for treating gastrointestinal (GI) fistulas associated with Crohn's disease (CD), a debilitating form of inflammatory bowel disease (IBD). Preclinical studies, clinical trials, and systematic reviews have evaluated the safety and efficacy of these approaches, with ADSCs-commercially available as Darvadstrocel-emerging as one of the most promising options. While notable progress has been made in both experimental and clinical research, the overall effectiveness of exosomes and stem cell-based therapies is still an area of active investigation. Further studies are needed to develop optimized, innovative treatments with minimal adverse effects. Given the substantial morbidity and healthcare burden associated with IBD-related fistulas, there is a critical need to find cost-effective, accessible, and reliable therapeutic options and strategies. Critically, none of these innovations will reach patients without regulatory convergence or cost-effectiveness data. Exosome therapies still lack a dedicated approval pathway, and GMP-scale purification is still confined to a handful of facilities, driving prices beyond current reimbursement limits. Future phase III trials must therefore embed economic modeling and adopt composite end points that link molecular engagement to MRI-verified fistula healing and patient-reported outcomes.