Fluffy hybrid nanoadjuvants for reversing the imbalance of osteoclastic andosteogenic niches in osteoporosis

Osteoporosis is majorly caused by an imbalance between osteoclastic and osteogenic niches. Despite thedevelopment of nationally recognized first-line anti-osteoporosis drugs, including alendronate (AL), their lowbioavailability, poor uptake rate, and dose-related side effects present significant challenges in treatment. Thiscalls for an urgent need for more effective bone-affinity drug delivery systems. In this study, we produced hybridstructures with bioactive components and stable fluffy topological morphology by cross-linking calcium andphosphorus precursors based on mesoporous silica to fabricate nanoadjuvants for AL delivery. The subsequentgrafting of -PEG-DAsp8 ensured superior biocompatibility and bone targeting capacity. RNA sequencing revealedthat these fluffy nanoadjuvants effectively activated adhesion pathways through CARD11 and CD34 molecularmechanisms, hence promoting cellular uptake and intracellular delivery of AL. Experiments showed that smalldoseAL nanoadjuvants effectively suppress osteoclast formation and potentially promote osteogenesis. In vivoresults restored the balance between osteogenic and osteoclastic niches against osteoporosis as well as theconsequent significant recovery of bone mass. Therefore, this study constructed a drug nanoadjuvant withpeculiar topological structures and high bone targeting capacities, efficient intracellular drug delivery as well asbone bioactivity. This provides a novel perspective on drug delivery for osteoporosis and treatment strategies forother bone diseases.