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Synergistic Effects of NO/H2S Gases on Antibacterial, Anti-inflammatory, and Analgesic Properties in Oral Ulcers Using a Gas-Releasing Nanoplatform

Yuanqi Chen,Kezheng Lei,Yinxi Li,Zhixiang Mu,Tengda Chu,Jiajun Hu,Bairui Zeng,Yi Wang,Jianliang Shen,Xiaojun Cai,Tianpeng Shi,Hui Deng

Oral mucosal wounds are more prone to inflammation due to direct exposure to various microorganisms. This can result in pain, delayed healing, and other complications, affecting patients' daily activities such as eating and speaking. Consequently, the overall quality of life for patients is significantly reduced. To address these challenges, we developed a multifunctional therapeutic nanoplatform, DATS@Arg-EA-SA, through the self-assembly of guanidinated dendritic peptides (Arg-EA-SA) that encapsulate diallyl trisulfide (DATS), a hydrogen sulfide (H 2 S) donor. The guanidine-rich surface of DATS@Arg-EA-SA efficiently neutralizes reactive oxygen species (ROS) in the ulcer microenvironment, generating nitric oxide (NO), which acts as the primary antimicrobial agent by disrupting bacterial membranes. Concurrently, the presence of glutathione triggers the release of H 2 S from DATS, providing supplementary antibacterial support. DATS@Arg-EA-SA effectively kills all bacteria, achieving results comparable to those of penicillin, a classical antibiotic. Moreover, it demonstrates superior sterilization efficacy against drug-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), significantly outperforming penicillin. Following the initial antimicrobial phase, the nanoplatform transitions into an anti-inflammatory stage. H 2 S, in synergy with NO, facilitates the conversion of M1 macrophages to M2 macrophages, thereby reducing the expression of inflammatory factors. Importantly, the combination of H 2 S and NO provides effective analgesia by downregulating the expression of TRPV1 and TRPV4, thus restoring normal dietary behaviors and improving the overall quality of life. This system ultimately promotes collagen fiber deposition and accelerates the re-epithelialization of the ulcer wound, positioning DATS@Arg-EA-SA as a promising gas-delivery nanoplatform for rapid wound repair in the clinical treatment. Statement of Significance Oral mucosal wounds are highly susceptible to microbial infections, leading to inflammation, pain, delayed healing, and a significant decline in quality of life. We developed a multifunctional therapeutic nanoplatform (DATS@Arg-EA-SA) via the self-assembly of guanidinated dendritic peptides encapsulating the H 2 S donor DATS, which exhibited antibacterial, anti-inflammatory, and analgesic properties. In the oral ulcer microenvironment, DATS@Arg-EA-SA generates substantial NO under elevated ROS levels, while glutathione triggers the controlled release of H 2 S. NO disrupts bacterial membranes as the primary antibacterial agent, with H 2 S providing synergistic antibacterial effects. Furthermore, H 2 S and NO synergistically promote the transformation of M1 to M2 macrophages, attenuating inflammation. Importantly, the combined action of H 2 S and NO alleviates pain by downregulating TRPV1 and TRPV4, supporting the restoration of normal dietary behavior and improving quality of life.