Harnessing M1-Polarized Macrophage-Derived Extracellular Vesicles and Artificial Nanovesicles for Targeted Cancer Drug Delivery

Macrophage-derived extracellular vesicles (EVs) have emerged as promising biomimetic platforms for targeted cancer drug delivery due to their biocompatibility, immune-modulatory properties, and tumor-homing capabilities. Among macrophage subtypes, M1-polarized macrophages exhibit potent anti-tumor functions characterized by pro-inflammatory cytokine secretion, improved antigen presentation, and the ability to remodel the tumor microenvironment (TME). Utilizing these properties, M1-polarized macrophage-derived EVs serve as cell-free therapeutic systems capable of delivering bioactive cargo while simultaneously promoting anti-tumor immune responses. However, the clinical application of natural EVs is limited by low yield, heterogeneity, and challenges in large-scale production. Artificial nanovesicles (ANVs) have been developed to address these limitations, offering improved scalability, compositional control, and reproducibility. This review provides an overview of macrophage differentiation and polarization, with a focus on the immunological profile and anti-tumor mechanisms of M1-polarized macrophages. It further discusses current methodologies for EV isolation and ANV generation, along with cargo loading strategies that balance encapsulation efficiency and vesicle stability. In addition, this review also emphasizes their targeting approaches, cellular uptake pathways, and the intracellular trafficking mechanisms that influence delivery efficiency and therapeutic outcomes. Key challenges, including standardization, biological barriers, and functional consistency, are critically evaluated. Emerging strategies that integrate vesicle engineering with personalized medicine underscore the potential of these systems to advance precision oncology.