Engineered nanomaterials and macrophages: Toxicity mechanisms and protective strategies.

Engineered nanomaterials (ENMs) have gained extensive applications across diverse fields, yet their potential cytotoxicity, particularly toward the immune system, raises significant safety concerns. As critical sentinels of innate immunity, macrophages directly interact with ENMs, making them pivotal targets for nanotoxicity studies. This review systematically addresses the interplay between ENMs and macrophages to advance their safe therapeutic utilization. We first delineate the cellular internalization mechanisms of ENMs and their influence on macrophage phenotypic dynamics. Key determinants of ENM toxicity are critically analyzed, encompassing their physicochemical properties (e.g., size, surface charge, and functionalization) and bio-nano interface transformations. Mechanistic insights into ENM-induced macrophage responses are comprehensively discussed, including reactive oxygen species (ROS) generation, pro-inflammatory cytokine secretion, polarization reprogramming, regulated cell death modalities, and innate immune memory establishment. Furthermore, we propose mitigation strategies through rational ENM design (surface engineering and stealth coatings), macrophage function modulation, and artificial intelligence-driven toxicity prediction frameworks. This work provides a mechanistic foundation for developing biocompatible ENMs while minimizing unintended immune consequences, offering translational guidance for nanotechnology applications in biomedicine.