Multifunctional hydrogel microspheres regulate the balance of osteoblastic-osteoclastogenesis to treat osteoporotic bone defects by the NFATc1/RANKL/MAPK signaling

Osteoporosis (OP) is characterized by diminished bone mass and increased skeletal fragility, representing a metabolic disorder. Osteoporotic bone defects (OBD) pose significant treatment challenges due to the active generation of osteoclasts (OCs) and the suppression of osteogenic differentiation. These complications impose a substantial burden on patients and the healthcare system. To address this issue, alendronate sodium (AS) was incorporated into Gelatin methacryloyl (GelMA), and then loaded with ligustrum officinale polysaccharide (LOP) to form GelMA-AS-LOP microspheres. These multifunctional hydrogel microspheres, characterized by their abundant void structures, offered continuous drug release. GelMA-AS-LOP suppressed OCs’ activity and formation, enhanced osteogenic differentiation and mineralization, and exhibited low visceral toxicity. Consequently, they ameliorated the pathological microenvironment associated with OP and facilitate OBD regeneration. The hydrogel microspheres achieved this by promoting osteogenesis and modulating the NFATc1, RANKL (via LOP), and MAPK (via AS) signaling pathways, resulting in a dual synergistic effect.