Ferrous sulfate-loaded hydrogel cures Staphylococcus aureus infection via facilitating a ferroptosis-like bacterial...

Hydrogels loaded with ampicillin, vancomycin or other antibiotics are one of the most widely used therapeutic agents for keratitis caused by Staphylococcus aureus. However, emergence of methicillin-resistant S. aureus (MRSA) makes infections harder to be treated by antibiotic-based hydrogels, urging the development of novel antibacterial materials. Inspired by mammalian ferroptosis, we determined the bactericidal effects of ferrous sulfate (FeSO₄) on S. aureus, and evaluated the therapeutic potential of FeSO₄-loaded hydrogel in a mouse keratitis model. The results showed that FeSO₄ facilitated ferroptosis-like cell death in S. aureus with the key characteristics of reactive oxygen species (ROS) generation and lipid peroxidation. Notably, FeSO₄ also efficiently killed persisters and MRSA, and eliminated biofilms of S. aureus. RNA profiles demonstrated that ferroptosis-related genes were significantly up-regulated, and the genes responsible for cell wall and cell membrane biosynthesis were down-regulated after exposure to Fe²⁺, supporting the occurrence of ferroptosis and cell lysis. We further prepared a FeSO₄-loaded hydrogel by using hyaluronic acid (HA) and ascorbate. The FeSO₄ hydrogel has the characteristics of injectability, self-healing, uniform distribution of Fe²⁺ in the three-dimensional gel structure, appropriate fluidity, high-water retention, high efficacy to kill MRSA, and excellent biocompatibility. In a mouse keratitis model, we showed that treatment of animals with FeSO₄ hydrogel led to a rapid recovery of from keratitis, prevented the dissimilation of MRSA to the lung, and alleviated systemic inflammation, demonstrating the therapeutic potential of FeSO₄ hydrogel. Taken together, our results indicated that FeSO₄ hydrogel is a promising alternative to current antibiotics-dependent therapeutic materials for the treatment of infections by MRSA.