Abstract
Intracellular delivery of protein therapeutics by cationic polymer vehicles is an emerging technique that is, however, encountering poor stability, high cytotoxicity and non-specific cell uptake. Herein, we present a facile strategy to optimize the protein-polycation complexes by encapsulating with linear-dendritic telodendrimers. The telodendrimers with well-defined structures enable the rational design and integration of multiple functionalities for efficient encapsulation of the protein-polycation complexes by multivalent and hybrid supramolecular interactions to produce sub-20 nm nanoparticles. This strategy not only reduces the polycation-associated cytotoxicity and hemolytic activity, but also eliminates the aggregation and non-specific binding of polycations to other biomacromolecules. Moreover, the telodendrimers dissociate readily from the complexes during the cellular uptake process, which restores the capability of polycations for intracellular protein delivery. This strategy overcomes the limitations of polycationic vectors for intracellular delivery of protein therapeutics.