Cell membrane-camouflaged double emulsion-based SNEDDS for targeted melanoma therapy using Inula viscosa

Metastatic melanoma is an aggressive skin cancer with limited treatment options. Inula viscosa (IV), a medicinal plant rich in anticancer compounds such as chlorogenic acid shows therapeutic potential; however, low water solubility and rapid clearance of chlorogenic acid limit its clinical application. This study developed double emulsions-based self-nanoemulsifying drug delivery systems (SNEDDS) loaded with Inula viscosa extract (IVE-G), further coated with membranes from SK-MEL28 metastatic melanoma cells to enhance solubility, stability, and tumor-specific targeting. The optimized double emulsions-based SNEDDS formulation (Capmul:Tween 80, 1:3 ratio) contained 33.90 mg of IVE-G and showed favourable characteristics, including a mean droplet size of ∼ 37 nm and a low polydispersity index (PdI < 0.30), indicating high homogeneity. These double emulsions-based SNEDDS were thermodynamically stable and resistant to dilution, suitable for injectable use. Coating with melanoma cell membranes increased particle size (∼ 48 nm) and shifted the zeta potential to -2.19 mV, confirming successful biomimetic camouflage. Cytotoxicity was assessed using the WST-1 assay. Double emulsions-based SNEDDS-encapsulated IVE-G demonstrated significantly greater cytotoxicity against cancer cells compared to the free extract (IC₅₀ 218.00 ± 5.40 μg/mL for free IVE-G versus IC₅₀ 17.00 ± 0.80 μg/mL for SNEDDS-IVE-G). Importantly, the membrane-coated formulation (SNEDDS-IVE-G-M) exhibited selective cytotoxicity toward SK-MEL28 melanoma cells (7.00 ± 1.10 μg/mL IC₅₀), with minimal effects on non-cancerous Balb/3T3 fibroblasts (IC₅₀ 258.00 ± 6.20 μg/mL) and RAW 264.7 macrophages (IC₅₀ 178.00 ± 1.20 μg/mL). This suggests the membrane coating enhances homotypic targeting, potentially improving cellular uptake by melanoma cells. In summary, SNEDDS camouflaged with melanoma cell membranes and loaded with Inula viscosa extract represent a promising dual strategy for metastatic melanoma therapy, offering improved drug delivery, selectivity, and reduced off-target toxicity.