Size-Dependent Immunomodulatory Effects of Fe3O4 Nanoparticles by Inducing Pro-Inflammatory Polarization of Macrophages to M1 Type

Tumor-associated macrophages (TAMs) are pivotal in shaping the immunosuppressive tumor microenvironment (TME). Reprogramming TAMs towards an anti-tumor M1 phenotype represents a promising strategy to enhance anti-tumor immunity. While Fe3O4 nanoparticles (NPs) possess immunomodulatory potential, the influence of NP size on macrophage polarization and the underlying mechanisms remain unclear. This study aims to systematically investigate the size-dependent immunomodulatory effects of Fe3O4 NPs and elucidate their mechanisms. We synthesized a series of Fe3O4 NPs of controlled sizes (5 nm, 10 nm, 30 nm, and 100 nm) via the polyol method. Among these, the 10 nm NPs demonstrated superior cellular uptake efficiency in macrophages. This enhanced uptake induced a significant increase in intracellular reactive oxygen species (ROS) levels. Subsequently, the elevated ROS activated the NF-κB signaling pathway, promoting M1 macrophage polarization. This polarization was evidenced by enhanced CD86 expression, increased nitric oxide (NO) release, and elevated secretion of pro-inflammatory cytokines. This study identifies 10 nm as the optimal size for Fe3O4 NPs to elicit their maximal immunomodulatory effects. Our findings establish a crucial size-design principle for the rational development of nano-immunotherapeutic agents and identify 10 nm Fe3O4 NPs as a promising candidate for TAM-targeted cancer therapy.