Stimuli-responsive lyogels are considered to be smart materials due to their capability of undergoing significant macroscopic changes in response to external triggers. Due to their versatile and unique properties, smart lyogels exhibit great potential in various applications such as drug delivery or actuation processes. While Poly-N-isopropylacrylamide (pNIPAM) is widely known as a thermo-responsive material, it also shows significant solvent-responsive swelling behavior. For the systems tested, polar solvents induce strong swelling due to hydrogen bonding with the amide group, nonpolar solvents lead to significant shrinkage of the lyogels. The aim of this study is to investigate and to model this behavior for future application in chemical or biochemical reactors. As a current area of research, incorporating smart lyogel technology into (bio-)chemical reactors facilitates the development of smart reactor systems. Applying thermodynamic modelling with the gE model COSMO-RS on the monomer or oligomers of pNIPAM, the correlation between solvent-polymer interactions and the degree of swelling can be observed. pNIPAM derivatives exhibit low infinite dilution activity coefficients (IDACs) in polar solvents with large degrees of swelling, while displaying an increase of IDACs in nonpolar solvents. Hydrogen bonds dominate the swelling behavior of lyogels not only in pure solvents but also in mixtures of solvents with varying polarity. Even in mixtures containing high amounts of nonpolar solvents, large degrees of swelling were observed due to the uptake of the polar solvent in the lyogel matrix. This effect can be observed in binary solvent mixtures but also in representative mixtures along an esterification reaction with varying carboxylic chain length of alcohol and carboxylic acids.