Mesenchymal stem cell-derived extracellular vesicles in the treatment of type 2 diabetes and its complications: current progress and future directions

Abstract

Type 2 diabetes (T2D) and its complications represent a complex disorder involving multiple pathophysiological processes. Although conventional therapeutic approaches partially regulate blood glucose, they fail to fundamentally reverse disease progression or effectively prevent complications. This review summarizes the current research advance and challenges of using different forms of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) in treating T2D and complications. It begins with an introduction to the characteristics of MSC-EVs. Subsequently, the mechanisms and therapeutic prospects of natural MSC-EVs are analyzed, with a focus on their roles in inflammatory modulation, tissue regeneration, and improving insulin resistance. Engineering MSC-EVs, covering strategies including optimizing MSC culture conditions, modifying EV contents, and establishing MSC-EV delivery systems based on bioactive materials are then discussed, which boost EV yield and quality while enhancing therapeutic efficacy. Current challenges, including the limited yield and high heterogeneity of natural MSC-EVs, as well as issues related to long-term safety, immunocompatibility, and large-scale production of engineered MSC-EVs are finally overviewed, with emphasizing artificial intelligence in guiding future research directions. These summaries are crucial for clinical translation of MSC-EVs and will ultimately provide T2D patients with an effective and safe treatment option.

1. Introduction

Type 2 diabetes (T2D) is a rapidly growing metabolic disorder that presents significant challenges to global public health owing to its intricate pathophysiological mechanisms and extensive complications. T2D arises from inadequate utilization or decreased efficiency of insulin [1]. The global prevalence of T2D is gradually increasing [2], which is estimated to reach 12.2% (783.2 million people worldwide) by 2045 [3]. The development of T2D is closely linked to insulin resistance and β-cell dysfunction [4], in which insulin resistance is pivotal in T2D pathogenesis [5], while β-cell dysfunction leads to abnormal insulin secretion [6]. In T2D, persistent hyperglycemic environment can trigger inflammation, localized hypoxia, and increased oxidative stress. These conditions contribute to various complications [7, 8], such as wound healing impairment, retinopathy, and osteoporosis (Fig. 1) [9–12]. Current treatment approaches of T2D include pharmacotherapy [13], exercise, and dietary management [14], which alleviate symptoms of the metabolic disorder but cannot reverse or fundamentally cure T2D and its associated multi-organ dysfunction [15]. There is an urgent need for the development of novel therapeutic strategies to enhance patient quality of life and slow disease progression for T2D.

Mesenchymal stem cells (MSCs) are characterized by plastic adhesion properties, self-renewal, immunomodulation, and multiple differentiation potentials [16]. They can be derived from a wide array of tissues and are extensively tested in therapeutic applications [17]. Notably, our research group has conducted a pilot clinical trial showing that MSC treatment for T2D patients has beneficial effects yet certain limitations, with its efficacy being influenced by the disease’s severity [18]. Therefore, it is essential to further elucidate the mechanisms by which MSCs effectively treat T2D and to optimize treatment strategies for severe cases based on these insights. In this context, our studies and others’ have further illustrated that MSCs exert regulatory and therapeutic effects on T2D metabolism by releasing extracellular vesicles (EVs) [19], nano-sized particles secreted by cells, enclosed by a lipid bilayer [20], present in biological fluids and involved in intercellular communication in physiological and pathological processes [21]. MSC-derived EVs (MSC-EVs) have shown immense potential in T2D treatment [22, 23]. Further investigation into the therapeutic targets of MSC-EVs and the development of targeted engineering strategies are expected to provide new methodologies for stem cell-based therapies for T2D [24, 25].