Biomaterial Scaffolds Loaded With Stem Cell‐Derived Extracellular Vesicles: An Emerging Cell‐Free Intervention for Diabetic Foot Ulcers

Abstract

Diabetic foot ulcers (DFUs) are chronic, non‐healing wounds that represent one of the most debilitating complications of diabetes, frequently progressing to severe infection, lower‐limb amputation, and increased mortality. Current clinical interventions largely focus on symptom management and wound protection but remain insufficient in achieving complete re‐epithelialization or restoring functional skin integrity. Stem cell‐based therapies have demonstrated substantial regenerative promise; however, their broader application is constrained by risks of immune rejection, challenges in sustaining long‐term cell viability, and difficulties in preserving stable cellular phenotypes during expansion. In response to these limitations, cell‐free approaches—particularly extracellular vesicle (EV)‐based therapies—have gained momentum as a next‐generation modality that captures the therapeutic benefits of stem cells while avoiding the drawbacks of cell transplantation. When integrated with advanced biomaterial scaffolds such as nanofibers or hydrogels, EVs can be delivered in a protected, controlled, and bioactive manner, yielding multifunctional dressings or patches that actively modulate the wound microenvironment to promote healing. This review synthesizes current evidence from in vitro, in vivo, and clinical studies on stem cell‐based and EV‐based therapies, with a focus on their synergy with biomaterial scaffolds for advancing the treatment of diabetic wounds.