Nanocarrier-Based Cell Nucleus Delivery of Therapeutic Proteins.

Mukherjee, Nayana; Sarkar, Ankan Kumar; Jana, Nikhil R · Nano Lett · 2026

basic_science · Level V

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Abstract

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.