Osteoporosis, a prevalent disease characterized by low bone density and increased fracture risk, poses significant health challenges for the elderly. Current treatments offer short-term benefits but are limited by long-term efficacy and adverse effects, highlighting the need for new strategies. Chondroitin sulfate polysaccharides (CS), a major component of the bone matrix, are crucial for bone and cartilage health. However, their role in osteoporosis is understudied due to the heterogeneity of natural CS. we found reduced CS levels in osteoporosis patients and developed CS4-NP, a self-assembled tetrasaccharide nanoparticle that mimics CS's structure. CS4-NP, which efficiently delivers the active CS4, significantly improves bone mass in ovariectomized osteoporosis models. It activates the Activating Transcription Factor 4-Cystathionine gamma-Lyase signaling axis in pre-osteoblasts, enhancing osteogenesis. our findings suggest that CS4-NP, an oligosaccharide-based nanomaterial, could address the limitations of current treatments and provide a viable strategy for osteoporosis.