Mobile sugar rings on polymer chains improve liver drug delivery
Researchers developed a drug delivery platform using polyrotaxanes where single sugar molecules can slide and cluster to target liver receptors. This avoids complex synthesis of traditional triantennary sugar clusters and may carry larger therapeutic cargoes. The approach mimics natural multivalent interactions.
The platform employs polyrotaxanes, supramolecular structures where cyclodextrin rings slide freely along a polymer axle. By attaching single GalNAc sugar units to these mobile rings, the system allows sugars to self-cluster upon encountering asialoglycoprotein receptors, replicating the multivalent binding of traditional triantennary clusters without their complex synthesis.
Testing demonstrated comparable or superior cellular uptake versus conventional triGalNAc systems, particularly in serum-rich environments. The platform proved effective in two applications: LYTACs for targeted protein degradation and CRISPR-Cas9 nanoparticles achieving roughly 25% gene knockdown of transthyretin in mice, suggesting broad utility for heavy therapeutic cargoes.
This approach could lower manufacturing costs and technical barriers for liver-targeted therapies, potentially accelerating development of gene-editing treatments and protein-degradation medicines for conditions like amyloidosis and other hepatic disorders. Patients may benefit from more accessible advanced therapies, while pharmaceutical developers could reduce production complexity. However, clinical translation remains early, and long-term safety and efficacy in humans are unproven. The platform's versatility may also extend beyond liver targeting to other receptor systems.