Atopic dermatitis (AD), also known as eczema or atopic eczema (Chovatiya 2023), is a chronic inflammatory skin disorder characterized by persistent or recurrent symptoms including intense pruritus, erythema, and epidermal peeling located on the flexural surfaces (Clebak et al., 2023, Frazier and Bhardwaj, 2020). AD affects approximately 20–30 % of infants, 15–25 % of children, and 5–10 % of adults, significantly impacting the quality of life for patients, as well as their families and caregivers (Goh et al., 2022). The choice of AD treatment regimen depends largely on disease severity.(Langan et al., 2020) At present the main treatments for mild to moderate AD patients are the topical application of anti-inflammatory drugs including corticosteroids and calcineurin inhibitors, light therapy and systemic immunosuppressants may be utilized for patients with moderate to severe or recalcitrant AD (Gatmaitan and Lee, 2023). However, prolonged or inappropriate use of these treatments may lead to adverse effects. For instance, corticosteroids can induce drug dependence and exacerbate symptoms upon discontinuation, whereas calcineurin inhibitors may cause skin irritation, including tingling and burning sensations (Chovatiya and Paller, 2021, Wang et al., 2022). These limitations underscore the urgent need for novel therapeutic approaches for AD.

Aucklandiae Radix (Mu Xiang in Chinese), the dried root of Aucklandia lappa Decne, is a traditional Chinese medicine used for the treatment of digestive disorders in clinics (Feng et al., 2024). Previous studies have indicated that the extracts of Aucklandiae Radix could effectively alleviate the symptoms of AD-like skin lesions in Nc/Nga mice (Lim et al., 2014, Yang et al., 2017). Costunolide (COS) is one of the major active ingredients in Aucklandiae Radix and has been confirmed to possess anti-inflammatory, anti-allergic, anti-oxidative, hair growth promoting, and anti-cancer properties (D. Y. Kim and Choi, 2019; Liu et al., 2021). A recently published article has demonstrated that the COS derivatives could alleviate skin injury symptoms and down-regulate the levels of T helper type 2 (Th2) cells-type cytokines in MC903-induced AD mice model via inhibiting the phosphorylation of the MAPK and NF-κB signaling pathways (Lu et al., 2024). In addition, COS could suppress the proliferative activity of CD4+ T cells, as well as the differentiation of CD4+ T cells into Th subsets through the ERK and p38 activities inhibition, indicating that COS may be a potential agent for the treatment of T cell-mediated immune diseases (Park et al., 2016). Xu et al. reported that COS can directly bind to NLRP3 to avoid the activation of NLRP3 inflammasome and show anti-inflammatory effects on the disease models including gouty arthritis and ulcerative colitis (Xu et al., 2023). However, the poor water solubility and low oral bioavailability of COS limit further application through oral administration (Alamoudi et al., 2023, Niu et al., 2021).

To address the poor solubility of COS, converting COS into solid nanoparticles is essential before its incorporation into microneedles (MNs). Nanosuspension (NS) represents a widely reported technique for enhancing the solubility and bioavailability of poorly soluble drugs through particle size reduction methods (Sampathi et al., 2023). To obtain nanoparticles of drugs, the top-down approach involves the breaking of drug particles by milling and/or homogenization, while the bottom-up approach generates nanoparticles from drug molecules in solution via the anti-solvent precipitation or evaporative precipitation method (Wu and Wang, 2022). We employed the antisolvent precipitation method in this present study, the most cost-effective bottom-up technique for NS preparation, wherein organic solvents containing water-insoluble drugs are mixed with an aqueous solution to produce drug nanoparticles, followed by the freeze-drying process to improve physical stability (Alshweiat et al., 2018).

Compared to oral administration, transdermal drug delivery systems (TDDS) can bypass pre-systemic metabolism, enhance systemic bioavailability and enable pain-free administration (Laubach et al., 2021). However, the formidable barrier characteristic of the stratum corneum leads to the failure in the effective systemic delivery of broad range of therapeutic molecules (Duarah et al., 2019). MNs have been developed to overcome the limitations (Parhi 2022). MNs are micron-sized (<1000 μm in length), conical, pyramidal, or multifaceted piercing protrusions that can create temporary channels in the stratum corneum via a minimally invasive manner, thus overcoming the skin barrier functionality and allowing the delivery of therapeutic compounds (Jang et al., 2021, Sartawi et al., 2022). There are 5 types of designed MNs currently including solid, coated, hollow, hydrogel-forming, and dissolvable microneedles (DMN), of which DMN are regarded as the safest transdermal delivery system due to excellent biocompatibility, biodegradability, and drug delivery capabilities (Xiang et al., 2023, Yan et al., 2020). In this study, we chose the representative hyaluronic acid (HA) as the material of DMN due to its biocompatible, non-immunogenic, and biodegradable properties ( Kim et al., 2020).

In this study, we prepared COS NS-M to enhance the apparent solubility and in vitro release rate of COS, which was subsequently incorporated into DMN for transdermal delivery. The COS-DMN formulation, administered at less than 10 % of the conventional oral dose, demonstrated significant efficacy in alleviating symptoms of DNCB-induced AD-like skin lesions in BALB/c mice. This work provides a unique strategy for efficient transdermal delivery of COS.