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Hydrogel-based burn wound dressings with excellent antibacterial, antifungal, and mechanical properties are ideal biomaterials to promote infected large burn wound healing. In this study, the hydrogel synthesized by repetitive freezing-thawing consists of poly (vinyl alcohol) (PVA), silk sericin (SS), and azithromycin (AZM), with genipin (GNP) as crosslinker. The FTIR showed that all hydrogel components were successfully blended. The swelling ratio, porosity, cell attachment, and proliferation improved with SS incorporation, while increased PVA content enhanced the mechanical performance of the hydrogel. The inclusion of AZM improved the antimicrobial property of the hydrogel towards Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, and Candida albicans. The hydrogel showed sustained SS and AZM releases as well as cytocompatibility on keratinocytes and fibroblasts. Furthermore, the hydrogel displays skin adhesion ability when freeze-dried. In the in vivo study using an infected mouse full-thickness burn model with a 10% total body surface area, it was shown that burn injury led to increased inflammatory cytokine responses and macroscopic and microscopic alterations in the spleen and liver. The kidneys, on the other hand, revealed neither change. Interestingly, the prepared hydrogel had a better burn wound healing effect than the commercial Tegaderm™ film dressing, minimizing systemic burn effects. Hence, this novel hydrogel is projected to be a promising candidate for accelerated healing of infected burn wounds. [ABSTRACT FROM AUTHOR]