Asymmetric mesoporous silica nanoparticles (MSNs) with controllable head tail structures have been successfully synthesized. The head particle type is tunable (solid or porous), and the tail has dendritic large pores. The tail length and tail coverage on head particles are adjustable. Compared to spherical silica nanoparticles with a solid structure (Stober spheres) or large-pore symmetrical MSNs with fully covered tails, asymmetrical head tail MSNs (HTMSNs) show superior hemocompatibility due to reduced membrane deformation of red blood cells and decreased level of reactive oxygen species. Moreover, compared to Stober spheres, asymmetrical HTMSNs exhibit a higher level of uptake and in vitro maturation of immune cells including dendritic cells and macrophage. This study has provided a new family of nanocarriers with potential applications in vaccine development and immunotherapy.