Sulfated polysaccharides target RANK Lys97 to inhibit osteoclast differentiation and reverse osteoporosis

Current osteoporosis treatments fail to balance bone resorption and formation. Here we show that engineered 2-N,6-O-sulfated chitosan (26SCS), a synthetic pentasaccharide, restores 115% bone mass (therapeutic) and prevents 66% bone loss, surpassing bisphosphonates by simultaneously suppressing osteoclastogenesis and promoting vascularized osteogenesis. Mechanistically, 26SCS targets K97 in receptor activator of nuclear factor-κB (RANK) through geometrically matched sulfate pairs, blocking RANK ligand (RANKL) signalling to arrest preosteoclast fusion while enhancing platelet-derived growth factor-BB (PDGF-BB) secretion via preserved preosteoclast viability to drive angiogenesis-coupled mineralization. Structural and functional analyses reveal that carboxyl groups in natural glycosaminoglycans such as heparin competitively bind K97, disrupting therapeutic specificity-a limitation overcome by 26SCS's carboxyl-free design and sequence-controlled sulfation. Unlike monosulfated analogues (2SCS/6SCS) that oversuppress osteoclastogenesis or lack pro-osteogenic effects, 26SCS's dual sulfation balances inhibition with trophic support. Thus, this work redefines glycosaminoglycan therapeutics via sulfation-patterned, topology-engineered biomaterials harmonizing bone metabolism.