Magnetoelectric-bioactive dual functions of MXene regulate macrophage M1-M2 sequential polarization to promote healing of infected wound

Macrophages play an indispensable role in infection resolution and tissue repair through dynamic M1-to-M2 phenotypic polarization. The polarization phenotype of macrophages can be regulated by different nano-biomaterials, but it still faces challenges in achieving sequential polarization of pro-inflammatory M1 and anti-inflammatory M2 through a single nanoformulation. In this study, we proposed an approach to regulate the M1-M2 sequential polarization of macrophages using transition metal carbide/nitride (MXene) nanosheets endocytosed by the cells as the only regulator. In vitro experiments demonstrated that endocytosed MXene nanosheets, leveraging their high electrical conductivity and magnetoelectric activity, generated electrical signals and produced reactive oxygen species (ROS) under a rotating magnetic field, thereby inducing M1 macrophage polarization. Upon magnetic field removal, the bioactivity of MXene nanosheets facilitated macrophage repolarization to the M2 phenotype. Furthermore, the mechanism underlying the regulation of macrophage polarization from M1 to M2 phenotype involves both inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway and activation of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway. In vivo experiments further proved that MXene nanosheets, under on-off rotating magnetic field stimulation, enabled sequential M1-to-M2 macrophage polarization, effectively promoting bacterial clearance and tissue regeneration. These findings highlight that this two-step sequential strategy targeting macrophages represents a promising approach for infected wound healing.