Dual‐Cascade Responsive H ₂ Se Delivery Nanogels Bearing Selenobenzamide as H ₂ Se Donor for the Treatment of Multidrug Resistant Bacteria Infections

Abstract Hydrogen selenide (H ₂ Se) as one of the endogenous gaseous signaling molecules for antibacterial gas therapy, faces limitations such as high‐dose toxicity and short half‐life. Herein, a polymeric H ₂ Se delivery nanogel (H ₂ Se‐NG) incorporated with aldehyde‐modified selenobenzamide (SeAs) is designed for multidrug resistant (MDR) related healthcare‐associated infections (HAIs) treatment. H ₂ Se‐NG facilitates a dual‐cascade responsive release of H ₂ Se over 72 h, effectively addressing the safety issues caused by the rapid hydrolysis of traditional inorganic H ₂ Se delivery methods. In vitro and in vivo studies demonstrate that nontoxic doses of H ₂ Se‐NG at 150 µg mL ⁻¹ not only eliminated over 99% of MDR bacteria and their biofilm within 8 h while reducing levels of proinflammatory cytokines postinfection. Additionally, RNA sequencing results reveal that the released H ₂ Se induces oxidative stress at infection site, kills biofilm‐embedded methicillin‐resistant Staphylococcus aureus (MRSA) and leads biofilm elimination by activating biofilm dispersion genes, suggesting the potential of H ₂ Se‐NG as a promising strategy in antibacterial gas therapy.