Nanoparticles are normally classified as "hard", mainly consisting of metal or metal oxide cores, or "soft", including polymer-based, liposomes and biomimetic nanoparticles. Soft nanoparticles have been studied in depth for drug formulation and therapeutic delivery applications, albeit hard nanoparticles may offer easier synthesis, smaller size and more effective tumor penetration. Among them, silica nanoparticles maintain excellent biocompatibility and biodegradability and can be finely adjusted in size and shape, easily produced in a large scale and functionalized or loaded with active molecules. To help filling the gap of a poor clinical translation of hard nanoparticles, we have designed and developed three different nonporous silica nanocarriers loading the chemotherapeutic doxorubicin within the core matrix, on the surface or both inside and outside, respectively. A comparative study was performed on drug loading and drug release, silica matrix degradation and nanodrug cytotoxic activity, highlighting unexpected correlation between the strategy adopted for drug incorporation and nanoparticle behavior in a physiological environment. This study offers a new insight on the impact of the choice of the prodrug nanoparticles on the kinetics and efficacy of drug delivery, which may encourage the scientific community in developing a new generation of drug delivery systems based on hard nanocarriers.