Osteoclast precursor cell membrane-engineered bone-targeting calcium carbonate nanoparticles for anti-osteoporosis therapy

Osteoporosis (OP) is a metabolic bone disease characterized by reduced bone mass and deterioration of bone microarchitecture, resulting in an increased risk of fragility fractures. Current anti-osteoporotic therapies are often limited by poor targeting efficiency, suboptimal therapeutic efficacy, and systemic side effects, which restrict their long-term clinical application. To address these challenges, we developed a biomimetic nanoparticle M@PL/ACC/Ad, featuring homologous targeting and acid-responsive drug release for the precise treatment of OP. M@PL/ACC/Ad consists of a calcium carbonate nanoparticles (ACC) core loaded with adenosine (Ad), a lecithin modification layer, and a coating derived from osteoclast precursor cell membranes. Owing to the homologous targeting capability conferred by the cell membrane coating, M@PL/ACC/Ad preferentially accumulates in osteoclast precursor cells. Upon exposure to the acidic microenvironment of osteoporotic lesions, the ACC core gradually degrades, enabling controlled release of Ad. The released Ad activates the A 2A adenosine receptor (A 2A R), subsequently enhances PKA signaling, suppresses NF-κB activation, and inhibits the expression of nuclear factor of activated T cells 1 (NFATc1), thereby preventing osteoclast differentiation and maturation. M@PL/ACC/Ad significantly inhibited osteoclastogenesis and reduced the formation of mature osteoclasts in vitro . Treatment with M@PL/ACC/Ad markedly alleviated bone loss and improved bone microarchitecture in an ovariectomized (OVX) mouse model of OP in vivo . Collectively, M@PL/ACC/Ad achieves efficient targeted therapy for OP through homologous targeting, acid-responsive drug release, and suppression of osteoclast activity, providing a promising therapeutic strategy for OP.