Natural Polysaccharide-Mediated Nano-Delivery Systems for Osteoporosis Therapy From a Gut-Bone Axis Regulatory Perspective.

Osteoporosis is increasingly recognized as a systemic disorder driven by multi-level regulatory imbalance rather than a bone-restricted disease. Current therapies mainly rely on anti-resorptive or anabolic agents, which often fail to restore long-term skeletal homeostasis. The gut-bone axis integrates intestinal barrier integrity, immune signaling, microbial metabolism, and bone remodeling, offering substantial therapeutic potential. Translating this insight into clinical strategies remains challenging. Natural polysaccharides, especially from traditional herbal medicines, function not merely as passive carriers but as active nanocarriers capable of modulating the gut-bone axis, highlighting their emerging role beyond conventional drug delivery. Polysaccharide-based nanocarriers integrate drug delivery with intestinal microenvironment modulation through their structural complexity, dynamic interfacial behavior, and prebiotic-like properties, facilitating coordinated regulation of intestinal barrier integrity, immune responses, and microbiota-derived metabolites, offering new avenues for osteoporosis therapy. We summarize how polysaccharide-mediated self-assembly converts noncovalent molecular interactions into biologically responsive delivery behaviors in the intestinal environment, and explore design strategies such as amphiphilic modification, polyelectrolyte complexation, and multicomponent co-assembly to improve the stability, bioavailability, and spatiotemporal activity of herbal small molecules. Beyond pharmacokinetic enhancement, these systems amplify intestinal signaling and transmit immune-metabolic cues to bone, providing promising directions for therapeutic innovation in osteoporosis.