Water-based detergent systems offer several advantages, over organic solvents, for the cleaning of cultural heritage artifacts in terms of selectivity and gentle removal of grime materials or aged varnish, which are known to alter the readability of the painting. Unfortunately, easel paintings present specific characteristics that make the usage of water-based systems invasive. The interaction of water with wood or canvas support favors mechanical stresses between the substrate and the paint layers leading to the detachment of the pictorial layer. In order to avoid painting loss and to ensure a fine control (layer by layer) of grime removal, water-based cleaning systems have been confined into innovative chemical hydrogels, specifically designed for cleaning water-sensitive cultural heritage artifacts. The synthesized hydrogels are based on semi-interpenetrating chemical poly(2-hydroxyethyl methacrylate)/poly(vinylpyrrolidone) networks with suitable hydrophilicity, water retention properties, and required mechanical strength to avoid residues after the cleaning treatment. Three different compositions were selected. Water retention and release properties have been studied by quantifying the amount of free and bound water (from differential scanning calorimetry); mesoporosity was obtained from scanning electron microscopy; microstructure from small angle X-ray scattering. To demonstrate both the efficiency and versatility of the selected hydrogels in confining and modulating the properties of cleaning systems, a representative case study is presented.