Bone Targeting Peptide–Calcium Coordination Complexes for the Treatment of Osteoporosis

ABSTRACT Current calcium supplement strategies focus on bone‐targeted delivery to reduce bone loss or enhance bone formation. However, peptide–calcium complexes generally lack clear cell selectivity. This study demonstrated that pea peptides (PP), which were rich in aspartic acid (Asp) and glutamic acid (Glu) residues, had the potential to regulate osteoblast function. Based on this property, a PP–calcium (PP–Ca) complex was constructed to enable targeted calcium delivery to osteoblasts. The results indicated that PP not only targeted the osteoblast surface, but also promoted osteoblast differentiation, increased alkaline phosphatase (ALP) activity, and enhanced calcium influx in a concentration‐dependent manner. Further transcriptomic analysis identified potential molecular targets and signaling pathways involved in the osteogenic effects of PP, suggesting that EGFR, as an important periosteal protein, may participate in its regulatory process and providing an important basis for subsequent mechanistic studies. In a glucocorticoid‐induced osteoporotic zebrafish model, PP‐mediated calcium delivery further promoted bone formation and increased bone mass. Collectively, these findings suggest that PP has great potential as an osteoblast‐targeted calcium carrier and may provide a new strategy for the intervention of bone formation‐related diseases.