Design and Factorial Optimization of Curcumin and Resveratrol Co-Loaded Lipid Nanocarriers for Topical Delivery

<b>Background</b>: Nanotechnology provides innovative strategies to enhance drug delivery and therapeutic efficacy through advanced nanocarrier systems. <b>Objectives</b>: This study aimed to develop and optimize a nanostructured lipid carrier (NLC) co-encapsulating curcumin (CUR) and resveratrol (RESV) using a fractional factorial design to develop a topical formulation with antioxidant and anti-inflammatory properties. <b>Methods:</b> NLCs were produced via hot emulsification followed by high-pressure homogenization, and their physicochemical characteristics, drug content, stability, release profile, antioxidant activity, skin delivery, and cellular compatibility were evaluated. <b>Results:</b> The optimized formulation exhibited an average particle size of approximately 300 nm, a polydispersity index below 0.3, and high drug loading for both compounds. Stability studies over 90 days revealed no significant changes in physicochemical parameters, confirming the formulation's robustness. In vitro release assays demonstrated sustained release of both actives, with 58.6 ± 2.9% of CUR and 97 ± 3% of RESV released after 72 h. Antioxidant activity, assessed by the DPPH and ABTS assays, showed concentration-dependent radical-scavenging effects, indicating antioxidant potential. Skin permeation/retention experiments using porcine skin showed enhanced retention of CUR and RESV within the tissue, with no detectable permeation, indicating suitability for topical delivery. In addition, in vitro cell assays using human keratinocytes showed concentration-dependent responses and acceptable cellular compatibility. <b>Conclusions:</b> Overall, this study demonstrates the successful application of nanotechnology and experimental design to develop stable and efficient lipid-based nanocarriers containing natural polyphenol for topical therapy targeting oxidative and inflammatory skin disorders.