Asymmetric single-hole mesoporous silica nanocages, which are eccentric hollow structured spheres and consist of mesoporous shell with an open hole on their surface, with uniform particle size (100–240 nm), have successfully been synthesized via a novel anisotropic encapsulation of the mesoporous silica. In this unique nanocarrier, the eccentric hollow cavity and big hole (∼25 nm) can serve as a storage space and passage for large guest molecules. Meanwhile, the uniform mesopores (2–10 nm) with a high surface area (∼500 m2/g) in the silica shells of the nanocages can provide storage space for small guest molecules. The obtained single-hole mesoporous nanocages can be endowed upconversion luminescence. The obtained upconversion nanoparticles functionalized eccentric single-hole nanorattles were used to codeliver bovine serum albumin and doxorubicin dual-sized guests. The release of the dual-sized guests can be well controlled independently by heat and near-infrared (NIR) light with the assistance of NIR to ultraviolet/visible (UV/vis) optical properties of upconversion nanoparticles and heat-sensitive phase change materials.