In this respect natural organic switchable derivatives are mostly attractive due to their ease processability and global lower general toxicity. In some previous contributions we have shown that natural curcumin and cyclocurcumin may indeed act as molecular photoswitches, undergoing E to Z isomerization under visible light irradiation. However, in these natural compounds, the isomerization is pretty slow and its chemical quantum yield is strongly environment dependent due to the competition between np* and pp* excited states. As a matter of fact, curcumin may also show interesting properties in term of O 2 generation, due to its efficient intersystem crossing (ISC) coupled with residual fluorescence, which may facilitate its cellular localization. Recently, we have shown that by opportunely modifying the chemical core of cyclocurcumin, by replacing the 2,3-dihydropyran-4-one core by a 2-6-substitued g-pyrone (Figure ), the photoisomerization efficiency is strongly enhanced whatever the medium. Experimental findings have also been rationalized and supported by the calculation of the PES of the most important excited state for the natural-occurring and the biomimetic compound. In the present contribution, we resort to a combination of experimental techniques and molecular simulation to understand the specific interaction of the Z and E-isomers of biomimetic cyclocurcumin analogous with lipid bilayers mimicking cellular membranes. The change in the membrane properties, observed in liposomes, vesicles, and monolayers, as well as the results of the enhanced sampling simulations confirm on the one side the internalization of the photoswitches in the lipid environment, and on the other side the efficient alteration of the artificial membrane structural parameters upon irradiation. The inclusion of opportune hydrophobic alkyl substituent at on side of the chromophore turned out to be fundamental to achieve an easier penetration into, and the formation of stable complexes with the artificial lipid membranes. Hence, our study provides a guide to the improved molecular design of biomimetic cyclocurcumin-based photo-switches presenting non-negligible therapeutic effect.