Lipid matrix composition-tuned nanoparticles for enhanced topical retinol delivery and anti-photoaging efficacy

Retinol (Ret), a hydrophobic vitamin A derivative, is widely used for skin rejuvenation, inhibiting the degradation of major extracellular matrix components such as collagen. Ret has been incorporated into lipid nanoparticles, such as liposomes, to improve stability. However, the long-term stability of these formulations under temperature variations as well as systematic optimization remain unknown. To overcome these limitations, we developed a retinol-loaded nanostructured lipid carrier (Ret-NLC) by optimizing the solid-to-liquid ratio (SL ratio) to enhance long-term stability, cellular delivery efficacy, and skin permeation. The formulation was optimized at an SL ratio of 6:4, achieving a particle size of approximately 200 nm and acceptable size distribution (polydispersity index, PDI ≈ 0.3). Ret-NLC stored at 25 and 4 °C maintained favorable dispersion characteristics during 12 weeks of storage, and in vitro release studies showed sustained release of Ret. In addition, among the tested SL ratios, Ret-NLC (6:4) exhibited the highest skin-mimetic membrane permeation, with an approximately 4.5-fold increase compared with free Ret, indicating suitability for the delivery of hydrophobic bioactive compounds to the skin. Biological evaluation revealed that Ret-NLC effectively reduced reactive oxygen species (ROS) and suppressed matrix metalloproteinase-1 (MMP-1) expression by 63.6%, which are key factors associated with skin aging and extracellular matrix degradation. Finally, Ret-NLC was incorporated into a cream formulation for practical applications. Compared with the Ret cream, the Ret-NLC cream exhibited improved formulation stability, while maintaining its physicochemical properties. Overall, these findings support the potential of Ret-NLC as a nanoplatform for delivering hydrophobic bioactive compounds in biopharmaceutical applications.