Graphene‐Based Nanomaterials in Immunotoxicological Evaluation: Insights Into Macrophage Polarization, Tissue Engineering, and Biomedical Applications

ABSTRACT Graphene‐based nanomaterials (GBNs) have emerged as promising platforms for biomedical applications, yet their clinical translation is largely governed by interactions with the immune system. Among immune cells, macrophages act as key regulators of the biological fate of GBNs through polarization toward pro‐inflammatory (M1) or anti‐inflammatory (M2) phenotypes. This polarization is strongly influenced by the physicochemical properties of GBNs, including structural characteristics and surface chemistry, and directly impacts nanomaterial clearance, biodistribution, immunotoxicity, and therapeutic efficacy. This review synthesizes recent studies examining how GBN properties dictate macrophage polarization and the resulting immunological outcomes. Evidence from in vitro and in vivo investigations demonstrates that controlled macrophage responses can support beneficial effects such as tissue repair and cancer immunotherapy, whereas inappropriate activation may lead to oxidative stress, cytotoxicity, and adverse immune reactions. These findings highlight the dual role of macrophage polarization in mediating both therapeutic potential and immunotoxicity risk. We emphasize the need for standardized immunological assays and rational design strategies to predict and modulate macrophage responses to GBNs. A clearer understanding of the relationship between GBN physicochemical properties and macrophage polarization is essential for minimizing immunotoxicity while enabling safe and effective therapeutic applications.