For years, targeting the liver's specialized surface receptors, asialoglycoprotein receptors (ASGPR), required constructing rigid, three-pronged sugar clusters known as triantennary N-acetylgalactosamine (triGalNAc). While effective, synthesizing these intricate architectures demands complex multistep chemical assembly. Moreover, conventional triGalNAc often struggles to transport heavy biological cargoes, such as gene-editing machinery and large antibody conjugates.

To overcome these hurdles, the team, led by Assistant Professor Toru Taharabaru and Associate Professor Taishi Higashi at Kumamoto University's Faculty of Life Sciences, engineered a mobile drug delivery platform using polyrotaxanes—supramolecular thread-like polymers in which ring-shaped cyclodextrin molecules can freely rotate and slide along a central axle chain.

Instead of chemically forcing sugars into a fixed triad, researchers attached simple single sugar units (monoGalNAc) to individual ring molecules. Thanks to the inherent mobility of the polymer backbone, the single-sugar rings automatically slide together and self-cluster upon encountering liver receptors, mimicking complex sugar triads without spatial mismatch and enhancing multivalent interactions.

In comparative cellular studies, this mobile "monoGalNAc-polyrotaxane" achieved cellular uptake efficiency comparable to—and in complex biological serum environments, superior to—conventional triGalNAc systems while vastly reducing manufacturing complexity.