Metal-based nanoparticles for reprogramming macrophage polarization: Advances in immunomodulatory nanotherapeutics

Macrophages, key players in the immune system, exhibit remarkable plasticity, polarizing into pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes in response to microenvironmental cues. This functional dichotomy is pivotal in the pathogenesis and progression of a wide array of diseases, including cancer, autoimmune disorders like rheumatoid arthritis, atherosclerosis, and tissue injury. Consequently, modulating macrophage polarization has emerged as a promising therapeutic strategy. Metal-based nanoparticles (MNPs) have garnered significant attention in this field due to their unique physicochemical properties, which enable them to function as both immunomodulatory agents and sophisticated drug delivery vehicles. This review provides a comprehensive overview of recent advancements in utilizing various MNPs including those based on gold (Au), silver (Ag), iron oxide (Fe₃O₄), manganese dioxide (MnO₂), titanium dioxide (TiO₂), molybdenum disulfide (MoS₂), zinc oxide (ZnO), and calcium carbonate (CaCO₃) to reprogram macrophage polarization for therapeutic benefit. We critically examine the distinct strategies employed; for instance, promoting a shift toward the M1 phenotype using Fe₃O₄ or TiO₂ nanoparticles to enhance anti-tumor immunity, versus inducing M2 polarization with Au or Ag nanoparticles to resolve inflammation and promote tissue repair. The underlying mechanisms, such as reactive oxygen species (ROS) modulation, targeted delivery of therapeutic payloads, and direct interaction with cellular signaling pathways, are discussed in detail. Finally, this review summarizes the therapeutic potential of MNPs in macrophage-targeted immunomodulation and highlights the existing challenges and future perspectives for their clinical translation.