Highly Branched Poly[dimethylaminoethyl methacrylate-co-bis(2-acryloyloxy) ethyl disulfide] for Efficient Intracellular Protein Delivery

Intracellular protein delivery holds great potential for the prevention and treatment of various diseases but remains challenging. Cationic polymers are promising candidates for protein delivery because of their highly tailorable chemical composition, topological structure, and terminal functionalities and thus are capable of navigating multiple extracellular and intracellular barriers. Here phenylboric acid (PBA)-functionalized, biodegradable, highly branched poly[dimethylaminoethyl methacrylate-co-bis(2-acryloyloxy) ethyl disulfide] [P(DM-co-DS)-E] were developed for efficient cytoplasmic protein delivery. The electrostatic interactions, nitrogen-boronate (N-B) coordination, and cation−π interactions between the DMAEMA units, PBA moieties, and protein facilitate protein packaging, leading to formation of nanosized, nearly neutral nanoparticles, while the disulfide bonds in the branching junctions impart biodegradability to promote protein release in the cytoplasm. In human chondrosarcoma (SW1353) cells, the optimal P(DM₁₀-co-DS₁)-E1 achieved up to 20-fold higher delivery efficiency compared to commercial PULSin, while maintaining high cell viability.