<p>Combined topical medicines with 5-fluorouracil (5-FU) and cerium oxide nanoparticles (CeO₂ NPs), which can act as a light filter, may be effective for the treatment and prevention of skin diseases such as actinic (solar) keratosis, Bowen’s disease, vitiligo and others. The main goal of this work was development and study of two gellan gels formulations with 5-FU that are insensitive to cerium ions. In accordance with the first methods of combined gel obtaining, initially CeO₂ NPs in gellan matrix were synthesized using ammonium cerium (IV) hexanitrate and meglumine. On second stage 5-FU containing transfersomes were introduced into CeO₂ NPs gellan gel. Transfersomes were obtained by hydration of a thin film of nonionic surfactant Tween-80 and lipoid S-100 in a mixture of chloroform-ethanol in phosphate buffer solution. Transfersomes had a diameter equaled to 89–167&#xa0;nm and zeta potential equaled to + 0.3 – −7.6 mV. Other combined 5FU-CeO₂ NPs gel was obtained by introducing maltodextrin-protected CeO₂ NPs synthetized by the polyol method into gellan gel, and then 5-FU was added too. The CeO₂ NPs properties were studied by EDX, PXRD, ICP-MS, laser dynamic light scattering (LDS), UV spectrophotometry. We investigated the release kinetics of 5-FU from combined gels using various mathematical models (zero-, first-, second-, and pseudo-second-order, Korsmeyer-Peppas, Higuchi, and Hixson-Crowell models). The release kinetics were found to be modeled using a pseudo-second-order equation (R² = 0.9983). It was estimated that combined transfersomal gels improve the release efficiency by 12 ± 2%. Therefore, transdermal delivery of 5-FU from a transfersomal gel or by protecting CeO₂ NPs with polysaccharides allows for the effective controlled release of 5-FU from a combined dosage form, which is promising for the treatment of various skin diseases.</p>