Allergic rhinitis (AR) is a common chronic inflammatory disorder of the nasal mucosa whose prevalence has been rising worldwide, posing a significant public health burden[1], [2]. Epidemiological data indicate that more than 500 million people are affected by AR globally, with adult prevalence ranging from approximately 10% to 30% and rates in pediatric populations exceeding 40%[3], [4]. The pathogenesis of AR primarily involves the binding of allergens to IgE receptors on mast cells within the nasal mucosa, triggering the release of pro-inflammatory mediators such as histamine (HIS), interleukins (IL), and tumor necrosis factor (TNF)[5]. These inflammatory factors collectively contribute to a cascade of pathological responses, including increased vascular permeability, glandular hypersecretion, and sensitization of nerve endings. Consequently, effective suppression of local nasal inflammation is a central strategy for the management of AR.

Mometasone furoate (MF) is a potent intranasal corticosteroid widely used in the clinical treatment of AR and recommended as a first-line therapy in international guidelines[6], [7]. Intranasal administration permits high local drug concentrations at the diseased mucosa to rapidly inhibit inflammatory mediators while minimizing systemic exposure[8], [9]. However, the clinical performance of intranasal sprays is often constrained by suboptimal particle distribution and deposition within the nasal cavity, and by the rapid mucociliary clearance of the nasal epithelium, both of which shorten nasal residence time and reduce absorption, thereby limiting bioavailability and clinical efficacy[10], [11]. In addition, the highly lipophilic nature of MF presents a notable challenge for formulation design aimed at achieving sustained intranasal action without compromising local or systemic tolerability[12]. Given these limitations, the development of delivery systems capable of prolonging intranasal residence while maintaining good tolerability is of considerable importance to enhance the local therapeutic efficacy of MF.

Although chitosan has been shown to markedly improve the mucoadhesion of particulate carriers in the gastrointestinal tract, its effectiveness in the nasal cavity is limited by important physiological differences between these sites[13]. In particular, the high mucociliary transport rate in the nose substantially reduces the contact time of drugs or carriers with the epithelial surface, compromising retention and efficacy[14]. Moreover, conventional chitosan relies on pH-dependent protonation of its primary amino groups (pKa ≈ 6.5) to achieve a positive charge; at the near-neutral pH of the nasal lumen (≈6.5–7.5) deprotonation occurs, leading to decreased charge density, reduced aqueous solubility and weakened mucoadhesive interactions compared with more acidic sites such as the stomach[15]. Consequently, traditional chitosan coatings that depend on pH-sensitive protonation may lose adhesive strength in the nasal environment, underscoring the need for pH-independent mucoadhesive strategies to prolong intranasal residence of liposome-encapsulated drugs such as MF.

Quaternized chitosan (QCS), a permanently cationic and more water-soluble derivative of chitosan, provides pH-independent mucoadhesion that can strengthen electrostatic interactions with nasal mucus and prolong carrier residence[16], [17]. When applied as a coating for liposomes, QCS can impart these advantages to the vesicular carrier, improving surface charge and colloidal stability in the near-neutral nasal environment. Compared to traditional chitosan, QCS has a higher charge density, which not only improves its adhesion to the nasal mucosa but also enhances its stability in the complex nasal environment. In addition, reported antimicrobial and anti-inflammatory properties of QCS may favorably modulate the nasal microenvironment and reduce local inflammation, further supporting sustained local drug retention and therapeutic effect.[18], [19]. Therefore, coating MF-loaded liposomes with QCS presents a promising strategy to achieve pH-independent nasal mucoadhesion and establish a local drug depot for improved treatment of AR.

In this study, a mucoadhesive nasal delivery system based on QCS-coated liposomes was designed to improve nasal retention, with MF encapsulated as a model drug (QCS–MF–Lip). The permanent positive charge of QCS enhances the affinity of the liposomes to the nasal mucosa, thereby improving the retention time of the drug in the local area. The primary objectives include optimizing the formulation and preparation process to enhance liposomal stability, prolong nasal residence time, and reduce mucus clearance, thereby improving the bioavailability and therapeutic efficacy of the drug. A systematic investigation was conducted to evaluate the nasal delivery characteristics of QCS-modified liposomes, focusing on their drug release profile, mucopenetration and retention behavior, and interaction mechanism with mucin, so as to elucidate the underlying mechanisms and advantages. Furthermore, pharmacodynamic studies in rats were performed to verify the superior efficacy and in vivo consistency of QCS-MF-Lip compared to commercial product Nasonex®, providing a solid scientific basis for its clinical translation. Preliminary safety and irritation assessments were carried out using ex vivo toad palate and rat nasal mucosa models to ensure the clinical safety and tolerability of the formulation. This innovative strategy offers an ideal drug delivery system for moderate-to-severe persistent AR and opens a new avenue to overcome the clinical challenges associated with MF therapy.