We have studied the thermal structural stability of liposomes encapsulating proteins by using synchrotron radiation small- and wide-angle X-ray scattering (SR-SWAXS). Liposomes are known to be effective drug-delivery systems (DDSs) because they can reduce drug toxicity due to biodegradability and biocompatibility and can offer promising carriers of various types of drugs. However, in spite of numerous studies of liposomes, physicochemical characteristics of liposomes entrapping proteins are rarely known. The liposome studied is characterized by the lipid composition (mixture of acidic glycosphingolipid (ganglioside)/cholesterol/phospholipid). Gangliosides are one of the major constituents of so-called lipid rafts playing the role of a platform of cell-signaling. We have found that the encapsulation of proteins elevates the thermal transition temperature of the liposome membrane and suppresses the deformation of its shape. The present results suggest that not only membrane proteins, but also water-soluble proteins affect liposome stability through the revalence between osmotic pressure and membrane elasticity. In addition, we have found the presence of the size-effect depending on the molar content of gangliosides in the liposome, indicating the ability of ganglioside molecule controlling both the size and effective surface charge of the liposome. The present results would have significance from two different points of view. One is the confinement effect of proteins within a limited space like cell, and the other is a stability of a new type of DDS using gangliosides. Due to the intrinsic properties, gangliosides are expected to be promising agents for targeting and long-circulation properties of liposomal DDSs.