AbstractHot-melt extrusion is an effective method for enhancing the solubility of weakly water-soluble compounds through amorphization, but the obtained powder form does not provide sufficient skin adherence or residence time, thus requiring incorporation into a suitable carrier for topical delivery. Hydrogels can serve as an appropriate carriers for such systems, offering additional characteristics such as self-healing and pH-responsiveness. Therefore, our research aimed to develop a hydrogel carrier with distinct features for a hot-melt extruded system containing curcumin and hesperetin, both having anti-cancer activity against skin cancer. We used a double cross-linking method with tannic acid and aluminum ions to prepare three hydrogels with different ratio of these agents, characterized by ATR-FTIR and rheological tests. Swelling studies in buffers of varying pH andin vitrorelease tests in pH 5.5 showed significant pH-responsive swelling and varying release rates of active compounds, influenced by cross-linking degrees. The prepared hydrogels swelled significantly, with percentages ranging from 170 to 4016%, with the maximum swelling at pH 5.5. Hesperetin release was measured as 84.92 ± 0.03%, 84.21 ± 1.21%, and 80.75 ± 2.76% in formulations H0, H1, and H2, respectively. While the release rate of curcumin increased with the degree of cross-linking, reaching 9.03 ± 0.07%, 26.43 ± 1.16%, and 27.31 ± 2.51%, respectively. In addition, a qualitative analysis with optical microscope confirmed the produced hydrogel's self-healing characteristics. Our findings provide a novel approach to improve the co-delivery of amorphous curcumin and hesperetin compounds to the skin.Graphical Abstract