MSC/MSC-EV therapy for chronic wounds: microenvironmental reprogramming, product design, and clinical translation

Chronic wounds are sustained not by a simple delay in the normal repair sequence, but by a hostile tissue microenvironment-persistent ischemia, non-resolving inflammation, proteolytic matrix degradation, oxidative stress, microbial burden, and senescence collectively form a self-reinforcing network that limits the effectiveness of conventional dressings and single-target interventions. Mesenchymal stromal cells (MSCs) and MSC-derived extracellular vesicles (MSC-EVs) are increasingly viewed not as replacement cells, but as transient, adaptive modulators of this pathological niche; their therapeutic effects are mediated largely through paracrine and vesicle-based signaling, which can recalibrate macrophage and T-cell responses, support angiogenesis, restore extracellular matrix homeostasis, protect resident keratinocytes and fibroblasts, and attenuate oxidative and infectious stress. This review reframes MSC-based therapy for chronic wounds as a product-design problem, synthesizing current evidence from wound biology, MSC and MSC-EV mechanisms, biomaterial-assisted delivery, source selection, potency testing, and early clinical studies, and argues that successful translation will depend on indication-matched products that couple defined biological potency with engineered delivery systems, clinically meaningful endpoints, patient stratification, and regulatory-ready manufacturing controls.