Extracellular vesicle-mediated cell-cell communication in keloids and hypertrophic scars: mechanisms, methodological...

Pathological scarring, including keloids and hypertrophic scars, remains a major clinical challenge characterized by persistent fibroblast activation, excessive extracellular matrix deposition, chronic inflammation, and aberrant tissue remodeling. Although current treatments have improved management, high recurrence rates and variable outcomes indicate that the underlying mechanisms remain incompletely understood. Extracellular vesicles (EVs), especially small extracellular vesicles (sEVs), are increasingly recognized as mediators of intercellular communication in fibrotic skin disorders. However, according to MISEV recommendations, the term "exosome" should be used cautiously unless endosomal origin is specifically demonstrated. In pathological scars, EV-/sEV-mediated signaling has been implicated in fibroblast activation, immune dysregulation, angiogenic imbalance, and extracellular matrix remodeling through cargo transfer among fibroblasts, keratinocytes, endothelial cells, immune cells, and mesenchymal stromal/stem cells. Reported downstream pathways include TGF-β/Smad, Wnt/β-catenin, PI3K/Akt, and NF-κB. However, the strength of evidence varies substantially, as many conclusions are based on in vitro studies or correlative omics analyses rather than direct causal experiments. In addition, differences in EV isolation and characterization methods may significantly affect reported cargo profiles and functional outcomes. This review critically summarizes EV-/sEV-mediated communication in keloids and hypertrophic scars, emphasizing vesicle nomenclature, methodological rigor, cell-specific signaling, and the distinction between causal and associative evidence. We also discuss translational challenges, including large-scale production, batch heterogeneity, storage stability, biodistribution, targeting, safety, and regulatory considerations.