Surfactant Ratio-Driven Modulation of Caffeine Loading and Release in <i>Nigella sativa</i> Oil Nanostructured Lipid Carriers

The delivery of hydrophilic actives such as caffeine through lipid-based topical carriers remains a challenge due to their poor affinity for lipophilic matrices and the barrier properties of the stratum corneum. This study investigated how the Tween 80/Span 20 surfactant ratio modulates interfacial organization, caffeine encapsulation, and release behavior of caffeine-loaded nanostructured lipid carriers (NLCs) formulated with <i>Nigella sativa</i> oil. Five NLC formulations were prepared with fixed lipid and surfactant concentrations, varying only in Tween 80/Span 20 ratio: NLC 1 (Tween 80 only), NLC 2 (Span 20 only), NLC 3 (1:2), NLC 4 (1.5:1.5), and NLC 5 (2:1). Physicochemical and functional properties were assessed, including particle size, zeta potential, entrapment efficiency, morphology, <i>in vitro</i> release, and occlusion factor. Intermediate surfactant ratios (1:2 and 1.5:1.5) achieved the highest entrapment efficiency (59.57 ± 5.43% and 63.22 ± 2.98%, respectively) with controlled release, suggesting interfacial structures that favor caffeine retention without excessively restricting diffusion. In contrast, Tween-rich systems showed lower entrapment efficiency and occlusion, consistent with looser, more hydrated interfaces. Zeta potential and transmission electron microscopy confirmed surfactant ratio-dependent interfacial structuring, while occlusion data suggested that intermediate surfactant ratio systems tended to form denser films, enhancing water retention. These findings demonstrated that surfactant ratio is not merely a stabilizing factor but a tunable design element governing the nanoscale organization of lipid-aqueous interfaces. By adjusting Tween 80/Span 20 ratios, formulators can balance retention, release, and occlusion, providing a rational framework for designing next-generation NLCs with improved performance and skin compatibility.