Targeting skin barrier repair: mechanisms of action, therapeutic evidence, and clinical translation challenges of mesenchymal stem cell-derived exosomes

Abstract

Dysfunction of the skin barrier is a central pathological feature in dermatology, driving the need for innovative repair strategies. Mesenchymal stem cell-derived exosomes (MSC-exos) represent a promising cell-free therapeutic paradigm, leveraging their innate cargo to modulate regeneration and immune responses. This review systematically examines the multifaceted role of MSC-exos in restoring skin barrier integrity. We delineate their molecular mechanisms in repairing physical, immunological, and microbial barrier components, supported by evidence from preclinical disease models. The influence of MSC source and preconditioning on exosome efficacy is analyzed, alongside emerging bioengineering approaches. Crucially, we identify and discuss the key translational challenges—including standardization, scalable manufacturing, and regulatory pathways—that must be addressed to advance these nanotherapeutics toward clinical application. This synthesis provides a critical framework for future research aimed at harnessing MSC-exos for targeted barrier repair.

1. Introduction

Mesenchymal stem cells (MSCs) are characterized by their capacity for self-renewal and multi-lineage differentiation. They can be isolated from various tissues, with bone marrow (BMSCs), adipose tissue (ASCs), and umbilical cord (UCMSCs) being the most extensively studied sources. Among these, umbilical cord– and placental–derived MSCs exhibit higher proliferative potential and are associated with fewer ethical concerns [1]. MSCs possess well-documented anti-inflammatory and immunomodulatory properties, coupled with low immunogenicity [2, 3]. Furthermore, their expression of various chemokine receptors enables targeted migration and homing to sites of tissue injury, where they participate in repair processes [4]. It is now established that the therapeutic effects of MSCs are mediated primarily through paracrine signaling, with exosomes serving as key effector vehicles of this action [5].

Exosomes are small, extracellular vesicles with a diameter of approximately 30–150 nm, released upon the fusion of multivesicular bodies with the plasma membrane [6]. They serve as pivotal mediators of intercellular communication, facilitating the horizontal transfer of bioactive molecules—including proteins, lipids, and nucleic acids (such as mRNA and miRNA)—between cells [6, 7]. This cargo is not randomly packaged; its loading into intraluminal vesicles within multivesicular bodies is a regulated process, primarily orchestrated by the Endosomal Sorting Complex Required for Transport (ESCRT) machinery [8]. The ESCRT complexes (ESCRT-0, -I, -II, -III) and associated proteins like Vps4 and Alix work sequentially to recognize ubiquitinated cargos, drive membrane invagination, and mediate vesicle scission [8]. Following their release, exosomes are characterized by a conserved set of membrane tetraspanins (e.g., CD9, CD63, CD81) and cytosolic proteins (e.g., TSG101, Alix), which are commonly used as identification markers [9].