Engineered solid lipid-polymer hybrid nanoparticles for trackable co-delivery of glycoalkaloids and Bcl-2/CD146-targeting of siRNAs: a topical formulation strategy for melanoma

The molecular complexity and adaptive resistance of melanoma limit the efficacy of conventional monotherapies, driving the development of multimodal therapeutic strategies. Here, we report the design and characterization of solid lipid–polymer hybrid nanoparticles (SLPHs) incorporating a FITC-labeled cationic polymer as a versatile platform for the co-delivery of a glycoalkaloid-rich extract (GE) and therapeutic small interfering RNAs (siRNAs) targeting Bcl-2 and CD146 in human cutaneous melanoma cells (SK-MEL-28). The engineered nanocarriers exhibited a hydrodynamic diameter of 217.3 ± 1.8 nm, narrow polydispersity (PdI = 0.137), and positive ζ-potential (+20.6 ± 1.1 mV), preserving colloidal integrity after lyophilization with sucrose (2.5% w/w). Confocal microscopy and flow cytometry demonstrated efficient cellular uptake and cytoplasmic co-localization of FITC-labeled SLPHs and AlexaFluor™-labeled siRNA (SLPH*-GE@siAF647). Ex vivo skin permeation confirmed penetration into the viable epidermis and superficial dermis. SLPH-mediated co-delivery achieved significant downregulation of Bcl-2 and CD146 (~83%) and shifted cell death away from pro-inflammatory necrosis toward apoptosis. Furthermore, freeze-dried SLPH-GE was successfully incorporated into a hydroxyethylcellulose hydrogel while maintaining physical stability. These findings establish SLPHs as a promising topical nanoplatform for localized gene-phytochemical combination therapy in cutaneous melanoma.