Polyplex nanovesicles of single strand oligonucleotides for efficient cytosolic delivery of biomacromolecules

Abstract Intracellular delivery of biomacromolecular drugs such as siRNA and proteins remains challenging. Polymers have been extensively explored as their delivery carriers, but the rigid structures and varied surface charges of siRNA and proteins make them hardly form well-defined nano-sized complexes with good stability for intracellular delivery. Here, we show that the flexible single strand oligonucleotides readily self-assemble with the poly(ethylene glycol)-b-poly( L -lysine) (PEG-b-PLL) into ~100 nm-sized nanovesicles, which can encapsulate siRNA and various proteins for efficient intracellular delivery. Moreover, a cytotoxic single strand oligonucleotide, polyfluoropyrimidine (F20), is used as a functional oligonucleotide. F20/PEG-PLL form nanovesicles (F20some) with fast cellular uptake, leading to significant higher cell cytotoxicity than naked F20 and the parent drug 5-fluorouracil (5-FU). Furthermore, F20some easily encapsulate siRNA and the cytotoxic proteins to potentiate the anticancer efficacy. The strategy in this study provides a promising platform for intracellular delivery of therapeutic oligonucleotides and other biopharmaceuticals.