This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility: Targeted drug delivery directly to the liver has unlocked major breakthroughs across medicine, but constructing the chemical key to enter liver cells remains complex and costly. Today, researchers at Kumamoto University, in collaboration with the National University of Singapore, have unveiled a nature-inspired solution that bypasses synthetic bottlenecks by giving single sugar molecules room to move.
Their findings are published in the journal Advanced Science. 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. The team demonstrated the platform's versatility across two cutting-edge therapeutic applications: "By leveraging molecular mobility, we allow the targeting ligands to flexibly adapt to the receptor's structure rather than forcing a rigid synthetic layout," Higashi says.
"This simple yet powerful approach provides a versatile, cost-effective platform to accelerate next-generation liver-targeted gene and protein therapies." Toru Taharabaru et al, Molecular Mobility of N ‐Acetylgalactosamine‐Modified Cyclodextrins on a Polyrotaxane for Highly Efficient Liver Targeting of Antibody Chimeras and Genome‐Editing Ribonucleoproteins, Advanced Science (2026). DOI: 10.1002/advs.75996 BA art history, MA material culture. Former museum editor, paramedic, and transplant coordinator.
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