Glycoalkaloids (GA) are secondary metabolites found mostly in higher plant species and some marine invertebrates. The effectiveness of these molecules against various cancer cells has been reported in the literature. One major problem that prevents their practical application is the hemolytic nature of GA. The possibility of employing mesoporous silica nanoparticles (MSN) to circumvent this problem is explored. Amino-functionalized MSN (MSN-NH2) coated with polydopamine (PD), and polyethylene glycol (PEG) were synthesized. The hemolytic activity of the nanoparticles (NP) was tested. PD and PEG-coated MSN showed no sign of hemolysis. Furthermore, the PEGylation of these MSN resulted in reduced phagocytosis. GA tomatine was loaded inside the pores of MSN-NH2. Thermogravimetry analysis (TGA) indicated a loading of 4.2%. The drug release profile of the DDS was tested at two different pH. A pH-dependent drug release with 3 times more tomatine being released at acidic pH of 5.5 compared to neutral pH of 7.4 was observed. The developed drug delivery system (DDS) showed a significant decrease in the hemolytic activity of tomatine. The effectiveness of the DDS was tested against human liver cancer (HepG2) cells and normal liver cells (THLE-3) between the concentration range of 0.4–12.7 μg mL−1 of tomatine loaded. Cell viability measurements demonstrated a comparable level of toxicity between the developed DDS and free tomatine. Further, the DDS was less toxic to normal cells at mid-range concentrations of 1.6 and 3.2 μg mL−1. The cancerous cells showed signs of late apoptosis. A decrease in the DDS-induced cell toxicity towards HepG2 cells upon the use of QVD-OPh, a polycaspase inhibitor, suggested that caspase-mediated apoptosis might be a plausible mechanism of cell death.