Protein Delivery to the Cytosol and Cell Nucleus via Micellar Nanocarrier-Based Nonendocytic Uptake.

Although efficient cell nucleus delivery of exogenous materials can greatly improve their biochemical activity, this is strictly restricted by cellular uptake and intracellular trafficking processes. In the current approach, synthetic carriers are designed for cell delivery of exogenous materials via endocytosis, and nucleus delivery can be achieved via endosomal escape. Here, we demonstrate that a nonendocytic cell uptake approach can be adapted for protein delivery to the cell nucleus. We have designed a phenylboronic acid-terminated micellar carrier that can bind with protein in the presence of green tea polyphenol and deliver protein into the cytosol via the nonendocytic approach. Using this approach, four different proteins are delivered to the cytosol within 15 min, and low-molecular weight proteins are delivered to the nucleus. The designed approach can be extended for delivering macromolecular drugs to subcellular targets for a more efficient therapy.

Nuclear Transport of the Molecular Drug via Nanocarrier-Based Nonendocytic Cellular Uptake.

Although subcellular targeting can enhance the therapeutic performance of most drugs, such targeting requires appropriate carrier-based delivery that can bypass endosomal/lysosomal trafficking. Recent works show that nanocarriers can be designed for direct cell membrane translocation and nonendocytic uptake, bypassing the usual endocytosis processes. Here we show that this approach can be adapted for the rapid cell nucleus delivery of molecular drugs. In particular, a guanidinium-terminated nanocarrier is used to create a weak interaction-based carrier-drug nanoassembly for direct membrane translocation into the cytosol. The rapid and extensive entry of a drug-loaded nanocarrier into the cell without any vesicular coating and affinity of the drug to the nucleus allows their nucleus labeling. Compared to endocytotic uptake that requires more than hours for cell uptake followed by predominant lysosomal entrapment, this nonendocytic uptake labels the nucleus within a few minutes without any lysosomal trafficking. This approach may be utilized for nanocarrier-based subcellular targeting of drugs for more effective therapy.