Sliding sugars offer simpler, smarter route to precision liver-targeted therapies
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…
Researchers at Kumamoto University and the National University of Singapore have developed a novel method for delivering drugs directly to the liver, marking a major breakthrough in precision medicine. The team, led by Assistant Professor Toru Taharabaru and Associate Professor Taishi Higashi, created a nature-inspired solution that simplifies the process of targeting liver surface receptors known as asialoglycoprotein receptors (ASGPR).
Traditional methods required complex chemical synthesis of rigid three-pronged sugar clusters called triantennary N-acetylgalactosamine (triGalNAc), which was costly and inefficient, especially for transporting heavy biological cargoes.
In contrast, the researchers engineered a mobile drug delivery platform using polyrotaxanes—supramolecular thread-like polymers where ring-shaped cyclodextrin molecules can move freely along a central axle chain. By attaching simple single sugar units (monoGalNAc) to individual ring molecules, the team eliminated the need for rigid sugar clusters altogether.
This mobility allowed the single-sugar rings to self-cluster and form multivalent interactions with liver receptors, achieving cellular uptake efficiency comparable to, and often superior to, conventional triGalNAc systems in complex biological serum environments.
This innovative approach not only streamlines the manufacturing process but also enhances therapeutic outcomes. The team demonstrated its effectiveness in two cutting-edge applications: delivering antibody chimeras and genome-editing ribonucleoproteins. The mobile monoGalNAc-polyrotaxane platform achieved comparable liver-cell uptake and demonstrated enhanced lysosomal protein degradation, leading to ~25% knockdown of the transthyretin gene in mice using CRISPR-Cas9 nanoparticles.
This groundbreaking method offers a cost-effective and versatile platform for next-generation liver-targeted therapies, paving the way for more efficient and targeted medical treatments.
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