In the context of cell–nanoparticle interaction, the question arises how ions influence the adhesion between nanoparticles and cell membranes. Here, the question is addressed how the adhesion energy between supported lipid bilayers and silica particles helps to understand nanoparticle uptake. Supported lipid bilayers on mica and glass substrates serve as simple, well‐defined, and reproducible membrane models. Using atomic force microscopy with modified cantilevers, the interaction energy of both is found to result in a distinctive dependence on the supporting material. The adhesion energy for 1,2‐dioleoyl‐sn‐glycero‐3‐phosphocholine on mica substrates shows a clear dependence on the NaCl concentration. On glass supports, in contrast, stronger adhesive forces lacking a systematic dependence are found. This is related to experiments where the uptake of silica nanoparticles in free‐standing vesicles is observed. While the qualitative dependence of the interaction strength on the ion concentration is definitely confirmed, the quantitative values of the adhesion energy can hardly be transferred to vesicles. These prospects and challenges also hold for investigations of more complex biological cell membranes in which increasing complexity inevitably also will increase the challenges. Due to the limited transferability of results obtained in situations of different symmetry and geometry, the combination of different methods is suggested.