High-altitude sleep disturbance is a manifestation of altitude sickness, mainly due to hypoxia (Ainslie et al., 2013) and characterized as low sleep quality, long sleep latency, and easy awakening (Guo et al., 2023). Persistent sleep disturbance gives rise to mood and cognitive impairments and eventually adverse effects on high-altitude operations (Cousins and Fernández, 2019). Benzodiazepines are the drugs mostly used to treat high-altitude sleep disturbance, but they have the drawback of dependence (Bushnell et al., 2022). Currently, acetazolamide is the only drug approved by the US Food and Drug Administration for the treatment of altitude sickness, but it still has such side effects as headache and nausea (Liu et al., 2017). Therefore, it is crucial to develop a safe and effective formulation to prevent high-altitude sleep disturbance.

Currently, studies on the mechanism of high-altitude sleep disturbance focus on neurotransmitters (Oh et al., 2019) and circadian rhythms (Shen et al., 2023). However, there are evidences that the brain, gut, and environment are closely related (Lv et al., 2022, Wang et al., 2021a, Wang et al., 2021b). For example, poor sleep quality is associated with dysbiosis of the gut microbiota (Matenchuk et al., 2020). The plateau environment affects the species richness of gut microbiota with increase in the relative abundance of Bacteroidetes and decrease in the relative abundance of Firmicutes (Lucking et al., 2018). As a dominant factor in the intestinal environment, gut microbiota not only affects gastrointestinal function (Ghosh et al., 2021), but also regulates the activity of the central nervous system by the neural, metabolic, and other pathways (Ding et al., 2020). Therefore, gut microbiota might be an important target for themodulation of sleep disturbance.

Quercetin (Que) is a natural flavonoid with multiple physiological activities, such as anti-inflammation and antioxidation properties (Lesjak et al., 2018). In addition, Que improves diseases related to nervous (Grewal et al., 2021), and digestive systems (Zhu et al., 2022), alleviates intestinal damages by increasing the expressions of intestinal tight junction proteins and altering the abundance of gut microbiota (Xu et al., 2021), and treats radiation-induced brain injury by regulating gut microbiota (Hu et al., 2023). Que is considered a potential drug for the prevention of high-altitude sleep disturbance. However, its clinical applications are severely hindered by its low solubility, poor dispersibility, and low bioavailability (Singh et al., 2021).

Drug nanosizing is an effective way to improve dispersibility of drugs and promote their absorption and utilization (Khan et al., 2022). Nomedicine has become well known for its role regulating the intestinal environment due to its small particle size and high drug-loading capacity (Vitulo et al., 2022). Zein, a main storage protein in corn, is a natural polymer and has good self-assembly characteristics. It can be constructed into nanoparticles in a variety of ways (Rodsuwan et al., 2020). It has received much attention in drug delivery because of its mucosal adhesion, biodegradability and low cost. Encapsulation of drugs into zein can facilitate controlled drug release due to the formation of aqueous channels during zein hydration and swelling (Wang et al., 2018). However, as nanoparticles accumulate in intestines, how to make drugs targeting the colon in the harsh gastrointestinal environment and achieve sustained release remains challenging. Natural polysaccharides such as sodium alginate (SA) and chitosan (CS) are biodegradable and bioadhesive materials, so that they have enormous potentials for colon drug delivery (Wang et al., 2016). Furthermore, CS modified with thiol groups can form disulfide bonds with colonic mucin, facilitating drug retention in the colon (Kiani et al., 2016).

Here, Que nanoparticles (QNPs) were prepared and characterized and they were loaded into calcium alginate hydrogel microspheres (QNP@HMs) for the prevention of high-altitude sleep disturbance. QNPs were conducive to drug accumulation and retention in the colon. QNP@HMs, with calcium alginate as the matrix and thiolated chitosan as the shell, could prevent drug degradation in the gastrointestinal tract and achieve colonic adhesion (Naeem et al., 2020). After physicochemical characterization, the efficacy of QNP@HMs was evaluated in a mouse model of high-altitude sleep disturbance. Additionally, the changes in the gut microbiota before and after administration were compared using 16S rRNA sequencing. This study provides a safe and convenient strategy for the efficient prevention of high-altitude sleep disturbance based on gut microbiota.