Advancements in extracellular vesicle targeted therapies for rheumatoid arthritis: insights into cellular origins, current perspectives, and emerging challenges

Abstract

Rheumatoid arthritis (RA) remains a challenging chronic autoimmune disorder characterized by persistent joint inflammation and damage. While modern regenerative strategies, encompassing cell/stem cell-based therapies, gene therapy, and tissue engineering, have advanced tissue repair efforts, a definitive cure for RA remains elusive. Consequently, there is growing interest in developing targeted therapies that directly address the underlying mechanisms driving RA pathogenesis, such as extracellular vesicles (EVs). These small membrane-bound particles can modulate immune responses within the inflammatory microenvironment of damaged cartilage. To launch the clinical potential of EVs, they can be isolated from various cell types through several techniques. EVs can carry various bioactive molecules and anti-inflammatory or pro-regenerative drugs, deliver them directly to the affected joints, and affect the behavior of injured cells, making them a compelling choice for targeted therapy and drug delivery in RA patients. However, there are still several challenges and limitations associated with EV-based therapy, including the absence of standardized protocols for EV isolation, characterization, and delivery. This review provides a comprehensive overview of the cellular sources of EVs in RA and delves into their therapeutic potential and the hurdles they must overcome.

1. Introduction

Rheumatoid arthritis (RA) is a prevalent chronic autoimmune disorder characterized by systemic inflammation and joint pathology, affecting around 1% of the global population. Notably, women are disproportionately impacted, being three times more susceptible than men. The disease manifests through synovial inflammation, autoantibody generation, and progressive bone and cartilage erosion, culminating in joint deformities and functional impairment, ultimately compromising patients’ quality of life. The pathogenesis of RA involves the interaction of various immune cells that secrete various pro-inflammatory and anti-inflammatory agents, affecting the patient’s synovial tissue and joints [1, 2].

Current therapeutic regimens for RA encompass nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids (GCs), nonbiological disease-modifying anti-rheumatic drugs (DMARDs), and biologic DMARDs (bDMARDs). However, prolonged usage often incurs adverse effects, ranging from gastrointestinal complications to heightened susceptibility to infections, alongside limited efficacy in a subset of patients, coupled with substantial financial burdens [3]. Recently, novel strategies, such as cell and extracellular vesicle-based therapy, have emerged as promising therapeutic approaches for various diseases, including RA. Extracellular vesicles (EVs) are lipid bilayer-bound structures secreted by almost all cell types, including immune cells, and carry various bioactive molecules, such as proteins, lipids, and nucleic acids. They play a crucial role in intercellular communication, immune regulation, and inflammation. In RA, EVs have been shown to have both proinflammatory and anti-inflammatory effects depending on their cellular source and cargo [4, 5]. Despite the promising therapeutic potential of EV-based therapy for RA, several challenges remain, including optimizing the isolation and characterization of EVs, determining the optimal cellular source and cargo for targeted therapy, and ensuring the safety and efficacy of the therapy in clinical settings [6]. In this study, we review new therapeutic advances in RA and discuss the perspectives and challenges of EV-based therapy for RA patients by focusing on cellular origins, current perspectives, and emerging challenges.