Label-free Nb4C3, Mo2Ti2C3, and Ta4C3 MXenes reprogram monocyte and macrophage activation toward an anti-inflammatory state.

Macrophages are central effectors of innate immunity whose plasticity supports both inflammation and resolution. However, their dysregulated activation underlies many inflammatory, infectious, and degenerative diseases. Here, we show that three two-dimensional MXene nanomaterials, Nb4C3, Mo2Ti2C3, and Ta4C3, are efficiently internalized by monocytes without compromising viability while reprogramming their activation and differentiation toward an anti-inflammatory macrophage state. Bulk RNA sequencing of murine monocytes treated with each MXene reveals a convergent transcriptional signature characterized by downregulation of proinflammatory genes (e.g., Cxcl9, Cxcl10, Ccl24, Il1b, and Il18), downregulation of Ccr2, and consistent upregulation of genes like Cd28 and Bhlhe41 across MXene treatments. At the protein level, secretion of CXCL10 and CCL24 is significantly reduced. Following early exposure of bone marrow precursors, differentiated macrophage cultures contained a larger CD86-CD206- fraction, fewer CD86+ and CD206+ cells, and reduced basal and LPS-induced activation, consistent with a less polarized, low-activation phenotype. Single-cell mass cytometry (CyTOF) enabled simultaneous immune profiling and label-free detection of MXene-associated elemental signals in peritoneal macrophage populations. In a thioglycolate-induced peritonitis model, MXene co-administration partially attenuated inflammation-associated changes in macrophage subset distribution. These findings establish MXenes as traceable immunoregulatory nanomaterials, enabling simultaneous control and tracking of macrophage responses in vivo. This work introduces a new nanoscale concept of compositionally encoded intrinsically traceable immunomodulatory nanomaterials that couple immune regulation and single-cell tracking even without surface labelling or drug loading.