Diffusion-mediated carving of interior topologies of all-natural protein nanoparticles to tailor sustained drug release for effective breast cancer therapy

Proteins are promising base materials for developing drug carriers with efficient blood circulation due to low possibilities of clearance by macrophages. However, such natural biopolymers have highly sophisticated molecular structures, preventing them from being assembled into nano-platforms with manipulable payload release profiles. Here, we report the self-assembly of two natural proteins (milk casein and rice protein) into protein nanoparticles (NPs, ∼150 nm) with tailorable release profiles. Diffusion of plant-derived paclitaxel (PTX)-containing eugenol into the hydrophobic cores of the NPs and subsequent dialysis to remove eugenol from the cores lead to the carving of the NP interiors. With the increase in the mass ratios of casein and rice protein, this process generates all-natural NPs with PTX loaded in their full cavities, semi-full cavities, or solid cores. These NPs can be efficiently uptaken by breast cancer cells and could kill the cancer cells efficiently. PTX in these NPs demonstrates increasingly sustained in vivo release profiles from full cavities, semi-full cavities, to solid cores, gradually extending its pharmacokinetic profiles in blood plasma to favor drug accumulation in breast tumor models. Consequently, the NPs with solid cores completely inhibit tumor growth in vivo, more effectively than those with full and semi-full cavities. Our work opens up a new avenue to the use of diffusion-mediated nanoscale carving in producing biomaterials with controllable interior topologies relevant to drug release profiles.