In this work, sub-50 nm pegylated mesoporous silica nanoparticles prepared with hydrothermal treatment are shown to have long-term stability in various media at both room and physiological temperature. Compared to bare mesoporous silica nanoparticles, the highly pegylated mesoporous silica nanoparticles show significantly improved biocompatibility and decreased macrophage uptake, making these nanoparticles viable for in vivo stealth drug delivery applications.