Cisplatin ( cis-diaminedichloroplatinum(II), CDDP) plays a crucial role in the treatment of various malignant tumors. However, its clinical efficacy and applicability are restricted by issues of toxicity and resistance. Here, for drug delivery purposes, the outer surface of MCM-41 mesoporous silica nanoparticles (MSNs) was functionalized with poly(ethylene glycol) ( Mw = 10 000 g/mol) or low-molecular-weight ( Mw = 1800 g/mol) branched polyethyleneimine (PEI). Given the strong affinity of sulfur for platinum, thiol-functionalized MSNs were synthesized for comparison by co-condensation with (3-mercaptopropyl)triethoxysilane. CDDP loading was performed either by adsorption or impregnation in aqueous media without the use of dimethyl sulfoxide as a solubilizer. CDDP loading capacities obtained by impregnation were higher than those obtained by adsorption and varied from 3.9 to 16.1 wt %, depending on the functional group. Loaded nanomaterials were characterized by scanning electron microscopy, scanning transmission electron microscopy-high-angle annular dark-field, and Raman spectroscopy. Depending on the functional groups, platinum-based species were either dispersed in the nanomaterials as nanocrystals or uniformly distributed as molecular species. The spectral signature of CDDP was strongly modified when platinum species were homogeneously distributed within the nanomaterials. Preliminary drug release studies performed at 37 °C showed that the behavior of CDDP-loaded MSNs strongly depends on the nature of the present functional groups. Among the functionalization routes investigated in this paper, PEI-based functionalization showed the most promising results for further applications in controlled drug release with the absence of burst release and a sustained release over 72 h.