Role of Extracellular Vesicles in Skin Barrier Repair: Applications in Atopic Dermatitis and Chronic Wounds

Leanne Khoo,1 Yun Zhi Chin,1 Jia Xian Law2 1Division of Applied Biomedical Science and Biotechnology, School of Health Science, IMU University, Kuala Lumpur, Malaysia; 2Department of Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, MalaysiaCorrespondence: Jia Xian Law, Email [email protected]: Extracellular vesicles (EVs) have emerged as a promising cell-free therapeutic strategy for skin barrier repair due to their ability to mediate intercellular communication through the delivery of bioactive cargo including proteins, lipids, and nucleic acids. This review synthesises current evidence on the role of EVs in restoring skin barrier integrity, with a particular focus on atopic dermatitis (AD) and chronic wounds. EVs derived from mesenchymal stromal cells, epidermal cells, and commensal microbiota exhibit distinct but overlapping therapeutic properties, including immunomodulation, promotion of keratinocyte proliferation and differentiation, and stimulation of dermal remodelling and angiogenesis. These effects are mediated through key signalling pathways such as AKT, ERK, NF-κB, Wnt/β-catenin, and HIF-1α/VEGF, as well as through regulatory microRNAs that fine tune cellular responses. Importantly, the relative contribution of these mechanisms is context dependent, with immune modulation predominating in AD and angiogenesis and tissue regeneration playing a central role in chronic wound healing. Despite strong preclinical evidence demonstrating efficacy, translation into clinical application remains limited by challenges in delivery, standardisation, and scalability. This review highlights the therapeutic potential of EV while emphasising the need for improved delivery strategies and rigorously designed clinical studies to fully realise their clinical utility in skin barrier repair. The infographic contrasts atopic dermatitis (inside-out barrier failure) with chronic wounds (outside-in barrier failure). Atopic dermatitis is linked to FLG mutation, Th2 immune skew and increased water loss, with therapeutic strategies focusing on immune modulation by shifting Th2 to Treg, reducing pro-inflammatory cytokines and restoring the lipid barrier. Chronic wounds result from external stressors like senescence and hypoxia, with treatments focusing on angiogenesis by increasing VEGF, ECM remodeling and M2 macrophage polarization. Both conditions impair the skin barrier, causing chronic inflammation and reduced life quality. Innovations for EV delivery include hydrogels, microneedles, nanofibres and nanoparticle carriers. However, ongoing clinical trials still focusing on free EV preparations. The main challenge is the delivery disconnect, where the ultimate goal is to restore homeostasis, enhance epidermal competence, and achieve functional wound recovery.Infographic on skin barrier failures: atopic dermatitis and chronic wounds, with innovation and therapeutic goals.Keywords: exosome, wound healing, mesenchymal stromal cell, angiogenesis, inflammation, epidermis