Secretory otitis media (SOM) is a type of non-suppurative inflammation of the middle ear characterized by tympanic effusion and hearing loss [1]. It has been reported that approximately 90% of preschoolers experience recurring episodes of SOM four times a year on average [2]. The standard treatment approach for recurrent SOM often involves the use of antibiotics, corticoids, and allergy treatment [3]. However, in cases where these conservative treatments fail to achieve desired outcomes, more invasive measures such as tympanostomy tube insertion and balloon eustachian tuboplasty may be necessary [4]. Although these methods can provide some beneficial effects, some patients exhibit poor responses, underscoring the need for new treatment strategies for SOM that balance both efficacy and safety [5].

Recent research has indicated that oxidative stress plays a key role in the common pathogenic pathway of SOM with effusion [[6], [7], [8]]. The microenvironment of SOM becomes overwhelmed with reactive oxygen species (ROS) and reactive nitrogen species (RNS), leading to oxidative stress, which is associated with many inflammation-related pathologies [9]. Especially, bacterial and viral infections in SOM trigger immune cells like macrophages and neutrophils to release ROS/RNS, resulting in protein denaturation, lipid peroxidation, and nucleic acid damage [10,11]. Antioxidants, including polyphenols, melatonin, vitamins, and others, have shown promise in inhibiting oxidative stress and may be beneficial in treating SOM [[12], [13], [14], [15]]. Astaxanthin (AST) is particularly noteworthy due to its antioxidant activity, which is 10-fold higher than beta-carotene and 100-fold higher than vitamin E [16]. However, its disadvantages of unstable inactivation, fast metabolism, and low bioavailability may yield a limited benefit [17]. To address these issues, researchers have explored nanoparticle-based delivery systems to enhance drug stability, prolong circulation in vivo, and target transport activity of the tympanic membrane [[18], [19], [20]]. These delivery platforms have been investigated for their potential in reducing the oxidative stress response of middle and inner ear [[21], [22], [23]]. Nevertheless, current AST delivery platforms still require improvements to enable intelligent and responsive drug release specifically in inflammatory microenvironments [24]. In our previous study, we successfully developed ROS-responsive Se-containing nanocarriers that exhibit the ability to load and deliver drugs in a controlled manner [25]. The incorporation of a diselenium bond as a ROS-responsive linker in these nanocarriers is particularly appealing due to its low bond energy of 172 kJ mol−1 [26]. This characteristic allows the diselenium bond to be easily broken upon exposure to ROS present in the inflammatory microenvironment. Subsequently, the oxidized diselenium bonds are converted into seleninic acid, facilitating the release of the loaded drugs [[26], [27], [28]].

Herein, we developed a novel delivery system for AST using apotransferrin (AFT) and a diselenium linker to address oxidative stress and regulate immune response in the treatment of SOM. As shown in Scheme 1, AST is encapsulated into diselenium cross-linked AFT nanoparticles, forming AST@dSe-AFT nanoparticles. AST@dSe-AFT exhibits a responsive release of AST specifically triggered by ROS present in the inflamed microenvironment of SOM. By the eradication of ROS, macrophages and neutrophils could be positively modulated from a pro-inflammatory phenotype to an anti-inflammatory phenotype, which reduces the levels of inflammatory cytokines in the SOM microenvironment. The use of AST@dSe-AFT demonstrates its potential for controlling local inflammation and promoting protective immune responses that facilitate the regeneration of tympanic mucosa. Overall, this work presents a novel strategy for suppressing inflammation and oxidative stress in the treatment of SOM.