Engineering a BMP2–risedronate complex with sustained release for osteoporosis therapy

Human bone morphogenetic protein 2 (BMP2) is a key inducer of osteogenesis; however, conventional delivery systems often result in burst release and adverse effects. To address this limitation, we fabricated an ionic complex of BMP2 with the clinically used osteogenesis inducer risedronate drug through an ion-pairing method. Fourier-transform infrared spectroscopy and ultra-resolution imaging confirmed the electrostatic interactions between BMP2 and risedronate. The resulting BMP2-risedronate complex exhibited a uniform particle size of 326 ± 149 nm, a polydispersity index of 0.2-0.3, and a zeta potential of - 38.08 ± 0.12 mV. The complex demonstrated a high complexation efficiency (˃ 95%). In vitro bioactivity studies using C2C12 myoblast cells demonstrated that BMP2, combined with risedronate, effectively induced osteoblastic differentiation. Furthermore, incorporation of the complex into 1.5% hyaluronic acid (HA) and 1% HA-19% poloxamer 407 (P407) hybrid hydrogel mitigated rapid release and retention, achieving a controlled release profile. In vivo studies confirmed that fabricated BMP2-risedronate complex loaded in hydrogels promotes sustained BMP2 release and, in combination with risedronate, enhances osteogenic efficacy. These findings suggest that the BMP2-risedronate ionic complex is a promising candidate for localized BMP2 delivery in osteogenesis therapy.