Ferrous gluconate-loaded sodium alginate hydrogel facilitates ferroptosis in Streptococcus hemolyticus and cures Streptococcal infections.

Streptococcus hemolyticus has recently regained public attention as "man-eating bacteria" and raised significant public health concerns due to the ever-increasing incidence of infections and severe toxic shock syndrome resulting from inadequate treatment. The growing challenge of antimicrobial resistance further emphasizes the urgent need for the development of novel wound dressings to prevent infections. This study demonstrated that ferrous gluconate (FeGlu) facilitated ferroptosis in S. hemolyticus accompanied with hallmarks of iron dependence, reactive oxygen species (ROS) burst, and lipid peroxidation. Moreover, the addition of inhibitors, including liproxstatin-1 (LIP-1), N-Acetylcysteine (NAC) and glutathione (GSH) hindered the happening of ferroptosis. In light of this, an antibacterial hydrogel was formulated by cross-linking FeGlu with sodium alginate (SA). This hydrogel exhibited excellent fluidity, self-healing properties, biocompatibility, and exceptional bactericidal efficacy. Furthermore, it displayed a superior therapeutic effect while posing no toxic risk in human skin fibroblast (HSF) cells. Proteomic analysis revealed that the FeGlu-hydrogel induced cell death by disrupting various pathways, including transmembrane transport, biomacromolecule synthesis, and cellular metabolism. Additionally, the FeGlu-hydrogel displayed a broad bactericidal spectrum against Streptococcus species, including Streptococcus pneumoniae and Streptococcus mutans. Collectively, these results proved that the FeGlu-hydrogel is a promising biomaterial for the treatment of Streptococcus-related infections.