Lactoferrin-cyanidin-3-glucoside nanoparticles alleviate inflammation and oxidative stress via Sesn2/Nrf2 activation in mastitis

Mastitis, driven by oxidative-inflammatory responses to <i>S. aureus</i>, lacks efficient therapies. Recently, protein-anthocyanin encapsulation has shown significant advances in biomedicine, but it faces structural stability/suboptimal efficiency issues, as well as an underexplored ROS-responsive targeting pathway. To address these issues, we engineered lactoferrin-encapsulated cyanidin-3-glucoside nanoparticles (LF-C3GNPs) using electrohydrodynamic nanotechnology for the management of oxidative-inflammatory disorders in mastitis. The NPs exhibited ROS-responsive C3G release, high colloidal stability, and H₂O₂-scavenging activity. In LTA- and H₂O₂-stimulated HC11 mammary epithelial cells, LF-C3GNPs attenuated inflammation and oxidative damage by activating <i>Sesn2/Nrf2</i> signaling, which enhanced antioxidant genes. LF-C3GNPs outperformed dexamethasone (DEX) in <i>S. aureus</i>-induced murine mastitis by reducing bacterial load and neutrophil infiltration, decreasing pro-inflammatory cytokines, and restoring redox balance. LF-C3GNPs showed excellent biosafety and hemocompatibility <i>in vivo</i>. LF-C3GNPs represent a potent nanomedicine for mastitis via <i>Sesn2/Nrf2</i> activation, with clinical translational promise. This study revealed significant anti-inflammatory and antioxidative effects of ROS-scavenging natural product self-assembled nanomedicine, offering a model for eco-friendly, efficient nano-antioxidant development to treat oxidative-inflammatory disorders related to diseases such as mastitis.