Extracellular vesicles for macrophage reprogramming: an emerging paradigm in immunomodulatory therapeutics

Macrophages are pivotal regulators of immunity, and due to their ability to differentiate into either pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes with remarkable plasticity, they can be used as strategies for treating diseases ranging from cancer to chronic inflammatory conditions. However, despite extensive research, the mechanisms driving macrophage polarization and the role of extracellular vesicles (EVs) in regulating these processes remain not fully understood. In particular, the specific signaling pathways and clinical applications of EV-mediated macrophage reprogramming are still under active investigation. Many recent studies have shown that EVs alter the immune environment by reprogramming macrophages to transition between M1 and M2 polarized states, thereby exhibiting therapeutic activity in a variety of diseases, including cancer. In addition, EV engineering aimed at improving macrophage reprogramming capabilities has been shown to enhance therapeutic efficacy, providing unprecedented opportunities to overcome previously untreatable diseases. This review addresses ongoing challenges by examining the latest findings on EV-mediated macrophage reprogramming and highlighting gaps in our understanding of the signaling mechanisms and clinical applications. We explore the signaling pathways and therapeutic potential of EVs in macrophage phenotyping, analyze evidence from disease models, and discuss how EV engineering strategies, including cargo loading and surface modification, expand their clinical use. Additionally, we consider critical factors for clinical translation, such as standardized production, immunogenicity, and safety. Overall, this review emphasizes the potential of EV-mediated macrophage reprogramming as a promising therapeutic strategy for immune-related diseases, while also addressing challenges and future directions for clinical application.