Dual-Cascade Responsive H₂Se Delivery Nanogels Bearing Selenobenzamide as H₂Se Donor for the Treatment of Multidrug Resistant Bacteria Infections

Hydrogen selenide (H₂Se) 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 H₂Se delivery nanogel (H₂Se-NG) incorporated with aldehyde-modified selenobenzamide (SeAs) is designed for multidrug resistant (MDR) related healthcare-associated infections (HAIs) treatment. H₂Se-NG facilitates a dual-cascade responsive release of H₂Se over 72 h, effectively addressing the safety issues caused by the rapid hydrolysis of traditional inorganic H₂Se delivery methods. In vitro and in vivo studies demonstrate that nontoxic doses of H₂Se-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 H₂Se 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 H₂Se-NG as a promising strategy in antibacterial gas therapy.