Mesenchymal stem cell-derived extracellular vesicles for disease therapy by regulating ferroptosis: focus on diabetes mellitus and diabetic complications

Abstract

Ferroptosis is a novel form of programmed cell death, which has been demonstrated to play a pivotal role in various pathological processes due to its association with iron overload, lipid peroxidation, and dysregulation of the antioxidant system. In recent years, mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have garnered significant attention as a promising cell-free therapeutic strategy for modulating ferroptosis. This article elucidates the biological characteristics of MSC-EVs and the molecular mechanisms underlying ferroptosis, with a focus on how MSC-EVs regulate ferroptosis through three key pathways: iron metabolism, lipid metabolism, and the antioxidant defense system. Additionally, the therapeutic potential of both natural and engineered MSC-EVs in treating ferroptosis-related diseases is discussed, particularly highlighting their efficacy in diabetes mellitus and diabetic complications. Finally, this article evaluates the challenges and opportunities in translating MSC-EVs-based ferroptosis modulation therapies into clinical applications, providing valuable insights for future research and therapeutic development.

1. Introduction

Mesenchymal stem cells (MSCs) are a type of multipotent stem cells derived from the mesoderm, with common sources including umbilical cord, bone marrow, adipose tissue, placenta, and dental pulp [1]. MSCs possess multiple characteristics, which lay a solid foundation for their therapeutic applications [2]. For instance, they exhibit the potential to differentiate into various mesodermal cells and, under certain conditions, can transdifferentiate into neural-like or epithelial-like cells across germ layers [3–5]. Additionally, they modulate immune responses through dual pathways: secretion of soluble factors and direct cell-to-cell contact. Moreover, they can sense chemokine gradients at injury or inflammatory sites via surface receptors and migrate directionally to diseased tissues to enhance therapeutic efficacy [6].

Currently, more studies have focused on mesenchymal stem cell-derived extracellular vesicles (MSC-EVs), which are nanoscale membranous vesicles secreted by MSCs, containing bioactive components such as proteins, nucleic acids, lipids, and metabolites. Their functions have been demonstrated in various disease models: (1) alleviating inflammation by regulating macrophage polarization (e.g., sepsis) [7]; (2) accelerating skin wound repair [8]; (3) promoting vascular network reconstruction in ischemic myocardium and regulating vascular homeostasis [9]; (4) rescuing neuronal apoptosis [10]; and (5) mitigating mitochondrial damage to improve acute kidney injury [11]. Compared to the limitations of MSCs, such as low differentiation efficiency and potential tumorigenic risks, these advantages of MSC-EVs—their high penetration and targeting capabilities, low immunogenicity and stability, and cell-free therapeutic safety—are particularly valuable [12]. According to various studies, the drug delivery strategies of MSC-EVs are also more diverse and better adapted to diseases, including: (1) targeted peptide/antibody modification [13, 14]; (2) exogenous drug/nucleic acid loading [15, 16]; and (3) integration with biomaterials or nanotechnology [17, 18].