Tannic acid (TA) is a hydrophilic polyphenol belonging to the family of tannins. Due to the presence of several functional hydroxyl groups, tannic acid is prone to interactions with cell structures, especially surface enzymes or receptor proteins. Here, different TANNylation methods were developed for the modification of mesoporous silica nanoparticles (MSNs) in order to investigate the impact of this surface functionality on the performance/biocompatibility of these nanocarriers. For the particle modification, a tannic acid silane linking-ligand was designed and subsequently installed on the MSN surface using post-grafting procedures. Grafting efficacy as well as the structural and physicochemical characteristics of the resulting particles were assessed. Then, two intestinal cell lines, HT29 and HCEC-1CT, were used for activity profiling, benchmarking the effect on the cytotoxic potential and endoplasmic reticulum (ER) stress response. The structure-activity relationships demonstrated that, in addition to the tannic acid itself, the different chemical linkers used for the binding of the polyphenol play an essential role in driving the biological response of intestinal cells. For equivalent TA concentrations, the type of coupling method not only strongly influences the grafting efficiency, but significantly alters the resulting ER response as well. The results underline that TANNylation is a promising method for enhancing cellular interactions with MSNs, although an adequate linking chemistry has to be implemented.