A novel one-step approach for designing non aggregated silica-based mesostructured therapeutic vectors is presented. Evaporation Induced Self Assembly was used in combination with amphiphilic drugs for preparing already loaded class I and class II hybrid materials containing from 50 to 60 wt% (up to 75 vol%) of drug. A good mesostructuration was able to promote an interfacial control of the drug release in PBS medium with a complete absence of the initial burst release very often described in literature for water soluble drug release experiments. The investigation of both release mechanisms and matrix dissolution was conducted via in situ ellipsometry and NMR. It proved that the nature of the drug/matrix interaction, the chemical composition of the drug/matrix interface, as well as the mesostructuration quality parameters must be taken into account at the same time for tuning the drug release rate, while maintaining the dissolution rate of silica at a reasonable level for limiting its toxicity. It proved also that non-calcined as made silica-based class I hybrid materials can be efficiently used for tuning drug release kinetics from one hour to day scale.