Obstructive sleep apnea (OSA), a prevalent disorder marked by recurrent upper airway obstruction during sleep, results in chronic intermittent hypoxia (IH)(Lévy et al., 2015). A growing body of evidence implicates IH as a principal contributor to OSA-associated cognitive impairment, mainly by promoting oxidative stress (Snyder et al., 2017; Zhang et al., 2024). The recurrent cycles of hypoxia and reoxygenation intrinsic to IH significantly promote the accumulation of reactive oxygen species (ROS), disrupting the homeostatic balance between pro- and anti-apoptotic signaling cascades (Shi et al., 2018; An et al., 2020). This redox imbalance, marked by diminished antioxidant defenses and enhanced lipid peroxidation, culminates in a sustained oxidative stress state (Nantachai et al., 2022). As a critical region for learning and memory, the hippocampus is highly susceptible to hypoxic damage owing to its intense metabolic activity and high oxygen requirement. Hippocampal neurons are particularly sensitive to oxygen fluctuations, with even brief hypoxic episodes capable of triggering rapid functional deterioration (Huang et al., 2015; Wang et al., 2022). Oxidative stress is well-established as a central mediator of neuronal apoptosis, leading to impaired synaptic plasticity and accelerating neurodegenerative processes (Akanchise and Angelova, 2023; Arias-Sánchez et al., 2023). Consequently, ROS elevation has emerged as a key pathological driver of IH-induced cognitive deficits. Alleviating oxidative stress offers a promising strategy for improving cognitive impairments associated with OSA (Fan et al., 2024).

Despite being the standard treatment for OSA, continuous positive airway pressure (CPAP) shows limited effectiveness in enhancing cognitive function. (Lv et al., 2023). Clinical studies have shown that CPAP does not significantly reduce oxidative stress markers (Paz et al., 2016; Montesi et al., 2012), suggesting that its mechanical effect alone may be insufficient to address the oxidative stress-related pathophysiology. Pharmacological agents such as modafinil and armodafinil have shown some benefit but are limited by side effects, poor bioavailability, and low permeability across the blood-brain barrier (BBB)(Smith et al., 2006; Lv et al., 2023). These limitations highlight the need for alternative therapeutic strategies. Accordingly, developing safe and effective antioxidants that can cross the BBB is essential for treating OSA-related cognitive impairment. Such approaches may help overcome current treatment limitations by directly targeting oxidative stress-induced neuronal damage.

Nanoparticle (NP)-based delivery systems offer a promising approach for antioxidant treatment in neurocognitive disorders (Vitaliano et al., 2022; Yang et al., 2022), as their small size and adjustable surfaces enable efficient BBB penetration via multiple routes without disrupting barrier integrity (Barbu et al., 2009; Xin et al., 2012). Once within the central nervous system, NPs can deliver antioxidant agents directly to neurons, effectively reducing ROS levels and mitigating oxidative damage (Wang et al., 2024).

To this end, we employed a bioactive ROS-Responsive nanoparticle (TPCD NP), synthesized by linking the antioxidant molecule Tempol and a phenylboronic acid pinacol ester to a β-cyclodextrin backbone (Li et al., 2018). Evidence from in vivo studies supports the biocompatibility of TPCD NP and highlights its robust antioxidative and anti-inflammatory effects in heart failure and ischemic stroke models (Yuan et al., 2021; Liu et al., 2021). Notably, its small size and ROS-responsive release enable efficient BBB penetration and targeted delivery to sites of oxidative injury, thereby reducing neuronal apoptosis. These features position TPCD NP as a promising therapeutic platform for mitigating oxidative stress-related neurodegeneration, particularly in the context of OSA-associated cognitive impairment.

This study explores the therapeutic potential and mechanistic pathways of TPCD NPs in OSA-induced cognitive impairment. A novel NP-based system is proposed to achieve efficient and targeted antioxidant delivery to the central nervous system. Using both in vivo and in vitro models, we will evaluate the ability of TPCD NPs to improve cognitive performance, reduce oxidative stress, and alleviate hippocampal neuronal injury under OSA-mimicking conditions. Overall, this work is expected to enhance our understanding of OSA-related neurocognitive dysfunction and support the development of NP-based antioxidant therapies.