Psoriasis is one of the most common immune-mediated chronic inflammatory diseases, presenting a significant public health challenge, with no complete cure. It is estimated that the disease affects more than 125 million people worldwide. Due to the deterioration of the patient's quality of life and physicosocial well-being, appropriate and effective treatment, along with long-term disease control, is essential. Presently, existing conventional medications aim to manage the condition and alleviate symptoms of psoriasis rather than providing a definitive cure. As a result, a significant challenge persists in finding novel drug compounds or delivery methods that can safely and efficiently manage psoriasis while ensuring patient adherence to the treatment regimen. Although traditional topical treatments for psoriasis are considered appropriate for mild cases, they present specific challenges, such as inadequate drug penetration into the skin, hyperpigmentation, and a burning sensation on both healthy and affected skin. In moderate and severe cases, it is necessary to prevent co-morbidities and cope with arthritis due to increased inflammatory effects. Therefore, evaluating different treatment options for psoriasis becomes crucial to address the diverse needs of patients [[1], [2], [3], [4]].

Despite the understanding of the inflammatory pathways involved in psoriasis and the development of some treatments that antagonize key cytokines, the etiopathogenesis of psoriasis has not been fully elucidated to date. It has been suggested that genetic and epigenetic factors, along with an impaired immune system, may contribute to the occurrence of the disease [5,6].

The most prevalent clinical manifestation of psoriasis is plaque psoriasis, also referred to as psoriasis vulgaris. In plaque psoriasis, there is an overactivation of the immune system, specifically the T-helper 17 (Th17) cell pathway. Th17 cells secrete IL-17, which induces the production of other pro-inflammatory cytokines, such as IL-6, IL-8, and tumor necrosis factor-alpha (TNF-α), further promoting inflammation and immune cell recruitment. IL-17 also stimulates keratinocytes to produce chemokines, which attract immune cells to the affected skin area. Additionally, IL-17 enhances the proliferation of keratinocytes and inhibits their differentiation, leading to the abnormal growth and thickening of the epidermis seen in psoriatic lesions [[7], [8], [9]]. Targeting IL-17 has emerged as an effective therapeutic approach in the treatment of plaque psoriasis. Medications known as IL-17 inhibitors, such as secukinumab and ixekizumab, have been developed to specifically inhibit the action of IL-17 and reduce inflammation in psoriatic skin. However, these biological agents have shown various side effects, including reactions at the injection site, upper respiratory tract infections, candida infection, the development of inflammatory bowel disease, hepatotoxicity, neutropenia, and malignancy. Additionally, patient compliance is low because they are administered intravenously [[10], [11], [12], [13]].

Psoriasis is considered a metabolic syndrome associated with dyslipidemia and an increased risk of cardiovascular disease. Patients with psoriasis often have high cholesterol and triglyceride levels [14]. Consequently, statin group drugs, such as fluvastatin used in the treatment of dyslipidemia, were thought to be useful in the treatment of psoriasis. Chen et al. demonstrated that the expression of galectin-7 in the skin lesions of patients with psoriasis decreased, and the expression of galectin-7 in keratinocytes was suppressed by cytokines responsible for the development of psoriasis. This resulted in both epidermal hyperplasia and keratinocyte-mediated inflammatory responses. Fluvastatin is a galectin-7 inducer that suppresses IL-6 and IL-8 production in keratinocytes induced by IL-17A. Thus, it has been suggested that the use of fluvastatin in the treatment of psoriasis may be beneficial [15].

The application of drugs to the skin with innovative colloidal delivery systems is an important approach in the treatment of various skin diseases. Phospholipid-containing vesicular systems are remarkable for topical and transdermal applications due to their biodegradability, amphiphilic nature, and ability to modify drug release. Among the various lipid-based vesicular systems, transethosomes have emerged as noteworthy candidates for enhancing drug delivery to the skin. The composition of transethosomes, which includes phospholipids, surfactants (edge activators), and ethanol, contributes to their potential as ideal carriers for overcoming the permeation barriers posed by the skin [16,17].

This study aims to formulate innovative, skin-compatible, and stable drug delivery systems that enhance the efficacy of psoriasis treatment by localizing the active substance in the targeted area of the skin. For this, topical transethosomes as colloidal drug delivery systems for the dermal administration of fluvastatin sodium (fluvastatin) in psoriasis treatment were prepared and the physicochemical properties, including particle size and size distribution, zeta potential, encapsulation efficiency, pH, conductivity, and stability were characterized. The structural and morphological properties of fluvastatin transethosomes were also analyzed by Attenuated Total Reflectance Fourier Transformed Infrared (ATR-FTIR) Spectroscopy and Transmission Electron Microscopy (TEM) and Scanning Electron Microscopy (SEM) analyses, respectively. Transfersome-type delivery systems were also prepared and characterized for comparison with the transethosome formulations. The in vitro skin penetration and deposition behavior of fluvastatin transethosomes were assessed using sequential tape stripping, Confocal Laser Scanning Microscopy (CLSM), and ATR-FTIR Spectroscopy, and compared to fluvastatin-loaded transfersomes. Furthermore, the cytotoxicity and antipsoriatic activities of the fluvastatin-loaded transethosomes in HaCat cells that exhibited the highest dermal accumulation were analyzed.