Biological barriers significantly limit the delivery efficiency of drug delivery systems, resulting in undesired therapeutic effects. When designing a delivery system with optimized penetration behavior across the biological barriers, mechanical properties, such as deformability, are emerging as important parameters that need to be considered, although they are usually neglected in current research. Herein, a liquid core nanoparticle (LCN) composed of a polymer-encapsulated edible oil droplet is demonstrated. Owing to the unique structure in which the liquid oil core is encapsulated by a layer of highly hydrophilic and cross-linked polymer, the LCN exhibits high mechanical softness, making it deformable under external forces. With high deformability, LCNs can effectively penetrate through several important biological barriers including deep tumor tissue, blood-brain barriers, mucus layers, and bacterial biofilms. Moreover, the potential of the LCN as a drug delivery system is also demonstrated by the loading and release of several clinical drugs. With the capability of penetrating biological barriers and delivering drugs, LCN provides a potential platform for disease treatments, particularly for those suffering from inadequate drug penetration.