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Targeted vault nanoparticles engineered with an endosomolytic peptide deliver biomolecules to the cytoplasm.

Vault nanoparticles were engineered to enhance their escape from the endosomal compartment by fusing a membrane lytic peptide derived from adenovirus protein VI (pVI) to the N-terminus of the major vault protein to form pVI-vaults. We demonstrate that these pVI-vaults disrupt the endosomal membrane using three different experimental protocols including (1) enhancement of DNA transfection, (2) co-delivery of a cytosolic ribotoxin, and (3) direct visualization by fluorescence. Furthermore, direct targeting of vaults to specific cell surface epidermal growth factor receptors led to enhanced cellular uptake and efficient delivery of vaults to the cytoplasm. This process was monitored with fluorescent vaults, and morphological changes in the endosomal compartment were observed. By combining targeting and endosomal escape into a single recombinant vault, high levels of transfection efficiency were achieved using low numbers of vault particles. These results demonstrate that engineered vaults are effective, efficient, and nontoxic nanoparticles for targeted delivery of biomaterials to the cell cytoplasm.