Gastric ulcer, a prevalent pathology within the digestive tract, is mainly characterized by the degradation of the gastric mucosa, often attributed to excessive gastric acid secretion and other harmful factors (Yang et al., 2021a, Lebda et al., 2021). The gastric mucosa is essential in maintaining the stomach's normal functions, such as its ability to withstand acids, alcohol, bile salts, and various foods (Wallace, 2008, Jones, 1987). However, sustained over-stimulation or stress on the stomach may increase gastric acid secretion, potentially leading to the erosion of the gastric lining, mucosal damage, and subsequently the development of conditions like gastritis, gastric ulcer, and even gastric cancer (Wu et al., 2022, Lu et al., 2022). Currently, the clinical treatment of gastric ulcers primarily involves the use of chemically synthesized anti-inflammatory drugs. Yet, the prolonged or excessive employment of non-steroidal anti-inflammatory drugs, including aspirin and ibuprofen, is known to exacerbate gastric acid secretion and impair the protective function of the gastric mucosa (Smith et al., 1991, Li et al., 2023). Consequently, there is an urgent need for the development of novel therapeutic approaches for gastric ulcer treatment. Scheme 1 represents the formation process of BSA·SH-DATS nanoplatform and its potential related mechanism of effective alleviation of ethanol-induced acute gastric injury in mice.

Gas therapy has recently emerged as a promising alternative to traditional treatments (Zhou et al., 2023). Utilizing endogenous gases such as hydrogen sulfide (H2S), hydrogen (H2), and carbon monoxide (CO), this approach has demonstrated significant potential in mitigating the inflammation commonly associated with standard therapies (Wang et al., 2020). These endogenous gas molecules, characterized by low toxicity, rarely cause systemic toxicity. The advancement of nanotechnology has been pivotal in expanding the applications of gas therapy, particularly through the development of nanomedicines that incorporate gases or gas donors. Research highlights that nanomaterials releasing H2S in response to glutathione (GSH) can effectively attenuate excessive inflammatory responses, including the downregulation of inflammatory factors and the transformation of M1 macrophages into the M2 type, thereby enhancing the inflammatory microenvironment in diabetic wounds (Xu et al., 2023). Glutathione, mainly found in the cytoplasm, constitutes a significant portion of its total concentration (Yoo et al., 2020, Vaskova et al., 2023, Fu et al., 2022, Couto et al., 2016). The interaction with reduced GSH leads to the disruption of disulfide bonds, initiating the bioactive functions of these molecules (Yang et al., 2022, Neves et al., 2016, Kim et al., 2020). An essential aspect of H2S therapy is the use of exogenous donors like diallyltrisulfide (DATS), derived from natural sources such as garlic. DATS is recognized for its ability to release H2S and has been extensively studied for its therapeutic implications (Benavides et al., 2007, Bradley et al., 2016, Ezeriņa et al., 2018, Cui et al., 2020).

Despite the effectiveness of H2S gas therapy, its practical application still faces challenges due to its volatile and unstable nature, making it difficult to utilize directly in medical treatments (Davis and Qian, 2019, Luo et al., 2019a, Efe et al., 2019). Implementing exogenous H2S donors like DATS for controlled H2S release and improving DATS's stability in the gastrointestinal tract also remains a challenge. In our study, we developed a facile nanocarrier by synthesizing bovine serum albumin-based nanoparticles (BSA·SH) through a thiolation chemical modification process. These BSA·SH nanoparticles were then functionalized with DATS via a Michael addition reaction, resulting in BSA·SH-DATS. In vitro experiments demonstrated that BSA·SH-DATS nanoparticles possessed excellent targeting capabilities towards GES-1 cells, along with pronounced anti-apoptotic and antioxidant properties. The effective reaction of DATS with intracellular GSH to produce H2S was confirmed using a WSP-5 fluorescent probe. Cryo-section imaging revealed significant accumulation of BSA·SH-DATS nanoparticles in the inflamed gastric tissues of mice, indicating targeted delivery. Furthermore, in vitro simulated digestion experiments showed a sustained-release effect of the BSA·SH-DATS in gastric juice. Meanwhile, Western blot analysis confirmed that BSA·SH-DATS nanoparticles could mitigate ethanol (EtOH)-induced apoptosis and inflammation in gastric tissues, as evidenced by the modulation of NF-κB and Caspase-3 protein expression levels. These findings suggest that the BSA·SH-DATS nanoparticle formulations hold significant promise as a therapeutic strategy for gastric ulcers, marking a novel advancement in the realm of nanomedicine-based drug delivery.