Purpose <p>This study presents the development of supramolecular nanosystems for the topical administration of rutin (RU), focusing on β-cyclodextrin (Cy) complexes and their inclusion in liposomes (CyL) in a 4:1 molar ratio.</p> Methods <p>The supramolecular nanosystems were obtained by the “thin film hydration” method, and characterized in terms of size, morphology, encapsulation efficiency, antioxidant activity and skin safety, by DLS, transmission electron microscopy, UV spectrometry, DPPH radical liberation assay and patch test, respectively. Rutin release kinetics was determined by Franz cell experiments.</p> Results <p>The resulting CyL loaded with RU formed stable, homogeneous vesicular dispersions, maintaining color, size, and polydispersity over 30 days, with rutin content consistently above 90%. Antioxidant activity, assessed by FRAP and DPPH assays, was significantly enhanced when RU was encapsulated in Cy and delivered via liposomes. In vitro diffusion studies using Franz cells revealed that CyL formulations provided a controlled release profile for RU, characterized by an initial increase followed by a plateau, suggesting vesicle-mediated release modulation. To improve topical applicability, CyL and Cy formulations were gelled with carbopol or xanthan gum, resulting in pseudoplastic, non-Newtonian gels. Gels containing CyL exhibited reduced spreadability and increased adhesiveness, supporting effective skin application. Patch tests on healthy volunteers confirmed good skin tolerability of all formulations.</p> Conclusions <p>These findings demonstrate that the combination of cyclodextrin complexation and liposomal encapsulation, followed by gelation, offers a promising dual strategy to enhance the topical delivery and antioxidant efficacy of rutin.</p>