Naturally occurring bioactive substances possess remarkable therapeutic potential with low toxicity. These compounds play a crucial role in defending host systems against viruses and environmental stressors. In recent years, extensive studies have highlighted the multifaceted benefits of numerous phytochemicals, including resveratrol (RSV), underscoring their potential in diverse therapeutic applications [1].

Resveratrol (trans-3,5,4′-trihydroxystilbene), a plant-derived flavonoid found in foods such as blueberries, cranberries, peanuts, cocoa, and notably in red wine [2]. It has multiple health benefits, including antioxidant, anti-inflammatory, antibacterial, antiviral, and anticancer properties [3].

Glioblastoma (GBM) is the most malignant and highly aggressive brain tumor, belonging to grade IV gliomas, according to the World Health Organisation (WHO) classification system. It is one of the deadliest cancers due to frequent recurrences within 6–9 months following surgical resection. Most GBM patients survive less than one year, and median survival time is only 8 months after diagnosis [4]. Therefore, it is critical to understand the invasion mechanism of GBM cells, to devise efficient therapeutic strategies. Given that in vivo animal models are complex, expensive, and time-consuming, various human GBM cell lines have been developed as in vitro models to study the complex interactions underlying glioblastoma progression and therapeutic responses [5].

With the rise of drug resistance, incorporating flavonoids into cancer therapy has emerged as a promising strategy. Among these compounds, resveratrol has garnered significant attention for its anticancer potential, first reported by Jang et al. (1997) [6]. RSV can cross the blood-brain barrier and influence brain physiology, with its anticancer effects involving the reduction of oxidative stress and inflammation, inhibition of cell proliferation, and activation of cell death mechanisms [7]. Numerous studies have documented RSV cytotoxic effects on brain cancer cells. For example, Zhang et al. investigated the impact of RSV on human U87MG glioblastoma and doxorubicin-resistant U87MG/DOX cells. Their findings showed that RSV inhibits glioblastoma cell progression and reverses chemoresistance, underscoring its potential as a promising treatment for brain cancer [8]. Additionally, RSV has been shown to mitigate the adverse effects of chemotherapeutic drugs [9,10]. When combined with other anticancer agents, RSV exhibits synergistic or additive effects, thereby improving the efficacy of these agents across various cancer types. In the case of GBM, the current standard treatment involves the oral administration of temozolomide (TMZ). Research by Yuan et al. revealed that RSV enhances the antitumor activity of TMZ in both in vitro and in vivo models. Specifically, in the human GBM cell line SHG44, the combination of resveratrol and temozolomide displayed additive antiproliferative effects [11].

Despite its promise, the application of resveratrol as a chemopreventive or therapeutic agent is limited by its low aqueous solubility, chemical instability, and poor absorption across biological membranes. To overcome these challenges, nanoparticle-based delivery systems such as liposomes have been developed to enhance its bioavailability. Liposomes are highly biocompatible carriers with versatile physicochemical properties and relatively simple preparation methods. They stabilize encapsulated substances, making them effective in entrapping, delivering, and releasing poorly soluble compounds. These advanced delivery systems enhance water solubility, stability, and membrane permeability, ensuring optimal concentrations of resveratrol reach tumour-target tissues. Additionally, they leverage the enhanced permeation and retention effect to improve efficacy at tumour sites [1].

The in vivo behaviour of a drug encapsulated in a liposome is influenced by various factors, including the liposome's physicochemical properties, such as zeta potential (ζ), surface charge density (ẟ), size, and lipid composition [12]. Zeta potential and surface charge play critical roles in mediating biochemical interactions, as evidenced by their growing relevance in diverse biochemical applications. Alterations in these electrical properties have been linked to membrane abnormalities, including those associated with cancerous transformations [13]. Understanding these parameters is vital for elucidating how resveratrol interacts with lipid membranes. Although the health benefits of RSV are well documented, its precise molecular mechanisms remain under active investigation. The cell membrane is considered a primary targets of RSV; however, an ongoing debate exists regarding its interaction with membrane lipids and its exact localization within the membrane structure [14]. Extensive research has been conducted to explore RSV's interactions and positioning within membranes, utilizing various experimental techniques and lipid models to account for the complex nature of cellular membranes. The results of these studies are varied; while some findings indicate that RSV is positioned within the hydrophilic headgroup region [[15], [16], [17]].- others suggest that it resides in the hydrophobic core of the membrane [18,19].

Limited attention has been directed toward the binding properties of RSV to lipid membranes. Therefore, this study aimed to investigate the electrophoretic behaviour of LN-18 glioma cell line and phosphatidylcholine liposomes in the presence of resveratrol. Specifically, we examined the impact of RSV on the electrical parameters characterizing these systems, including surface charge density and zeta potential, as a function of pH- one of the key factors influencing these properties. We employed the Electrophoretic Light Scattering technique, increasingly utilized in drug delivery research, nanoscale physical chemistry, biotechnology and other advanced scientific fields [20]. Our study combined experimental measurements with a theoretical analysis of interactions within the glioma cell membrane. Quantitative descriptions of equilibria in the analyzed systems enabled the determination of key interaction parameters, such as membrane surface charge densities, association constants, and the total surface concentrations of acidic and basic groups. Additionally, we assessed cell viability using the MTT assay to evaluate the effect of RSV on treated glioblastoma cells.