The physicochemical properties of nanoparticles (size, charge, and surface chemistry, etc.) influence their biological functions often in complex and poorly understood ways. This complexity is compounded when the nanostructures involved have variable mechanical properties. Here, we report the synthesis of liquid-filled silica nanocapsules (SNCs, ∼ 150 nm) having a wide range of stiffness (with Young’s moduli ranging from 704 kPa to 9.7 GPa). We demonstrate a complex trade-off between nanoparticle stiffness and the efficiencies of both immune evasion and passive/active tumor targeting. Soft SNCs showed 3 times less uptake by macrophages than stiff SNCs, while the uptake of PEGylated SNCs by cancer cells was independent of stiffness. In addition, the functionalization of stiff SNCs with folic acid significantly enhanced their receptor-mediated cellular uptake, whereas little improvement for the soft SNCs was conferred. Further in vivo experiments confirmed these findings and demonstrated the critical role of nanoparticle mechanical properties in regulating their interactions with biological systems.