Skin carcinoma is a highly perilous form of cancer that was initially documented by Laennec in 1804 for melanoma, Jacob in 1827 for basal cell carcinoma, and Bowen in 1912 for squamous cell carcinoma in situ [[1], [2], [3], [4]]. According to the World Health Organization, skin carcinoma ranks as the fifth most frequently reported cancer globally as of 2020. According to a report released by the American Academy of Dermatology (AAD) in 2022, it was revealed that an estimated 9500 individuals in the United States receive a diagnosis of skin cancer daily [5]. The UV light, which emits cancer-causing photons, is a well-known cause of skin cancer. This radiation causes reactive oxidative stress, resulting in direct or indirect DNA damage, which contributes to the formation of skin cancer [6].

Quercetin (QUR) (2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4-Hchromen-4-one), a flavanol categorized among the six flavonoid compound subgroups, is found in a variety of fruits and vegetables, including berries, lovage (Levisticum officinale), capers (Capparis spinosa), cilantro (Coriandrum sativum), dill (Anethum graveolens), apples (Malus domestica), and onions (Allium cepa) [7]. Because of its numerous beneficial qualities, including their anti-inflammatory, eyes, arthritis, chemo preventive, chemotherapeutic, and antioxidant capabilities, phytochemicals like quercetin have attracted enormous interest in the pharmaceutical research community [8,9]. Various research has shown chemoprotective action of QUR against cancer cells through apoptosis and metastasis, thus making it a promising choice for treatment of cancer [10,11]. Although QUR has a considerable significant pharmacological relevance, its low stability, rapid metabolism, quick absorption, poor aqueous solubility and quick systemic elimination limit its medicinal use [12].

Because of its poor aqueous solubility (≈2 μg/mL) and adverse effects, the oral delivery of QUR often results in reduced adherence among patients. Hence, it is necessary to develop a topical formulation that can effectively overcome these concerns, leading to enhanced aqueous solubility, aided skin permeability, controlled drug release and enhanced targeted delivery [13]. The topical route of administration has several potential advantages when compared to other routes. These benefits include the ability to bypass first-pass hepatic metabolism, prolong the duration of action, reduce the occurrence of undesirable side effects, enhance pharmacological effectiveness, and improve patient adherence. The topical route of drug delivery is particularly noteworthy for its effectiveness in cases where long-term or chronic medication therapy is required [14,15]. Within this context, it has been demonstrated that nanoparticulate delivery methods are efficient in preserving, managing the release, and amplifying the effects of various bioactive substances. In particular, liposomes have been thoroughly investigated and found to be highly valuable for skin delivery, particularly when it comes to lipophilic substances, since they facilitate improved drug deposition in the skin layers [16]. However, these formulations' stability and encapsulation effectiveness pose significant barriers to liposomal distribution [17].

Currently, there has been a notable surge in interest surrounding the utilization of nanoparticle formulations containing quercetin, owing to their potential in effectively addressing multiple aspects associated with the treatment of skin cancer. Prior studies have investigated various nanoparticle carriers for quercetin [18,19]. Our primary goal is to lead the advancement of liposome and transferosome, with the specific aim of overcoming the obstacles related to the management of skin cancer enhancing the efficacy to the deepest layers. Our study aims to optimize the effectiveness, depth of penetration, and targeted distribution of quercetin within the skin by utilizing the benefits of liposomes and transferosomes offering a new and innovative approach for skin cancer management.

For this reason, the current study aims to develop QUR-loaded transliposomes (QUR-TL) and incorporate them into Carbopol gel base to make an easier application of QUR on skins. The transliposomes as drug delivery carrier is a novel strategy that combines the advantageous properties of transferosomes and liposomes [17]. In addition to improved deposition properties and permeation ability, the addition of edge activator to the vesicles of transliposomes also increase the solubility and stability of drug [20]. The incorporation of TL into the gel base could perhaps result in an increase in the formulation's viscosity, which would last longer for the formulation at the application site.

We developed QUR-loaded TL for skin cancer management by ethanol injection method followed by sonication, formulation was further optimized by Box-Behnken design (BBD). The optimized QUR-TL formulation was further evaluated for various characterization parameters including the vesicle size distribution, surface charges (zeta-potentials), morphology by Transmission Electron Microscopy (TEM), in vitro release of entrapped drug, texture analysis, skin permeation, dermatokinetics and antioxidant studies.