Tetrandrine-loaded manganese-doped ceria nanozyme for nebulized inhalation therapy of the ROS-driven inflammatory-fibrotic continuum

Pulmonary fibrosis (PF) and acute lung injury (ALI) represent mechanistically interrelated stages along a shared inflammatory-fibrotic disease continuum, both driven by dysregulated macrophage responses and reactive oxygen species (ROS)-mediated signaling. Effective intervention requires a strategy that targets common upstream pathogenic drivers while addressing disease-specific downstream consequences. Here, we developed a tetrandrine (TET)-loaded manganese-doped ceria nanozyme (CMT) for targeted pulmonary delivery via nebulized inhalation and systematically evaluated its therapeutic effects across both disease stages. CMT exhibited favorable aerodynamic properties and retained potent multi-enzyme mimetic antioxidant activity. In vitro, CMT modulated M1/M2 macrophage polarization, inhibited macrophage-to-myofibroblast transition (MMT), attenuated fibroblast activation, and promoted myofibroblast apoptosis. In vivo, nebulized CMT significantly attenuated LPS-induced ALI and bleomycin-induced PF, reducing inflammation, collagen deposition, and fibrotic markers. Mechanistically, CMT suppressed both TGF-β1/Smad3 and NF-κB signaling—two key downstream pathways associated with ROS-mediated inflammatory and fibrotic responses—and showed greater therapeutic effects than either TET or the nanozyme alone. These findings support an integrated nanozyme-drug strategy that combines ROS scavenging, pharmacological regulation, and localized pulmonary delivery to target shared pathogenic mechanisms across acute and fibrotic lung injury.