Nitric Oxide-Releasing S-Nitrosoglutathione-Conjugated TEMPO-Oxidized Nanocellulose Hydrogel for the Treatment of MRSA-Infected Wounds

<b>Background</b>: Cutaneous wound infections caused by methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) pose serious threats to public health. Nitric oxide (NO), an endogenous gaseous molecule with antibacterial and wound-healing properties, is a promising next-generation antimicrobial agent with a minimal risk of resistance. However, conventional <i>S</i>-nitrosoglutathione (GSNO)-loaded formulations suffer from GSNO leakage, which could compromise the treatment effect or induce systemic side effects. Although conjugation strategies have been introduced to mitigate this issue, there is still a lack of GSNO-conjugated systems that simultaneously achieve high NO loading and sustained NO release while avoiding harsh external stimuli and complex multistep synthetic processes. <b>Objectives</b>: This research aims to develop a high NO-loading system produced through a simple synthetic process that provides sustained NO release without harsh external stimuli while preventing GSNO leakage for effective treatment of MRSA-infected wounds. <b>Methods</b>: We developed cellulose-based GSNO conjugates via a simple EDC/NHS-mediated covalent coupling to TEMPO-oxidized nanocellulose (NC-GSNO). <b>Results</b>: The NC-GSNO hydrogel achieved high NO loading, minimal leakage, and sustained NO release for more than three days. This controlled NO delivery promoted enhanced wound healing in MRSA-infected models. <b>Conclusions</b>: These findings demonstrate that the NC-GSNO hydrogel is a promising platform for controlled NO delivery and the effective treatment of MRSA-infected wounds.