A Cu⁺/Thiourea Dendrimer Achieves Excellent Cytosolic Protein Delivery via Enhanced Cell Uptake and Endosome Escape

Intracellular protein delivery has attracted considerable attention in the development of protein-based therapeutics, however, the design of highly efficient materials for robust delivery of native proteins remains challenging. This study proposes a Cu⁺ -based coordination polymer for cytosolic protein delivery with high efficacy and robustness. The phenylthiourea grafted dendrimer is coordinated with cuprous ions to prepare the polymeric carrier, which efficiently bind cargo proteins via a combination of coordination, ionic and hydrophobic interactions. The incorporation of Cu⁺ ions in the polymer greatly improves its cellular uptake and endosomal escape. The cuprous-based coordination polymer successfully delivered a variety of structurally diverse proteins into various cell lines with reserved bioactivities. This study provides a new type of coordination polymers for cytosolic delivery of biomacromolecules.