Nanocarrier-Based Cell Nucleus Delivery of Therapeutic Proteins

Delivering proteins into subcellular compartments can significantly enhance their therapeutic potential. However, such delivery is largely restricted due to poor cell uptake and lysosomal trafficking/degradation of delivered proteins. The direct membrane penetrating nanocarrier-based nonendocytic approach offers new opportunities for subcellular delivery of proteins. Here, we report histidine-terminated 2 nm gold nanoparticles as carriers for nucleus delivery of proteins via direct membrane penetration and temporary membrane pore formation while bypassing endosomal/lysosomal trafficking. It has been observed that successful nucleus delivery requires modular protein–carrier assembly of <50 nm size. Thus, nucleus delivery performance is sensitive to protein molecular weight and the ratio of protein to carrier concentration. Results show that nuclear delivery of proteins offers ∼2 times enhanced therapeutic performance as compared to their cytosolic delivery via the endocytic approach. The presented approach can be adapted to other therapeutic proteins and macromolecules for more efficient therapy.