Molecular Mobility of N ‐Acetylgalactosamine‐Modified Cyclodextrins on a Polyrotaxane for Highly Efficient Liver Targeting of Antibody Chimeras and Genome‐Editing Ribonucleoproteins

ABSTRACT Triantennary N ‐acetylgalactosamine ( tri GalNAc), which interacts strongly with the trimeric structure of asialoglycoprotein receptors (ASGPRs), is a validated platform for liver targeting. However, the intricate design and synthesis of its linkers impose high production costs and significant technical challenges. In this study, we report an alternative strategy for targeting ASGPR using monovalent GalNAc ( mono GalNAc) conjugated to the cyclic molecules of polyrotaxane, which can rotate and translocate along the axial polymer chain. The intracellular uptake efficacy of mono GalNAc‐modified polyrotaxane is comparable to that of tri GalNAc‐modified polyrotaxane and significantly higher than that of tri GalNAc‐ or mono GalNAc‐modified immobile control polymers. These results suggest that the inherent mobility of polyrotaxanes allows mono GalNAc moieties to cluster in a trivalent‐like manner, thereby enhancing multivalent interactions with multiple ASGPR oligomers. The successful application of mono GalNAc‐modified polyrotaxane to lysosome‐targeting antibody chimeras and genome‐editing nanoparticles demonstrates that this facile technology is a highly promising alternative to conventional tri GalNAc.