Development of icariin-loaded bone-targeting liposomes and its anti-osteoporosis effects and mechanism

Osteoporosis increases fracture risk, necessitating safe therapies. Icariin has anti-osteoporosis effects but exhibits poor solubility, short circulation, and lack of bone targeting. We developed tetracycline (TC)/1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol) (DSPE-PEG) co-modified liposomes (Icariin-TC-DSPE-PEG-L) to deliver icariin. Formulation variables (phospholipid/cholesterol, phospholipid/icariin, and phospholipid/TC-DSPE-PEG ratios) were optimized using an orthogonal experimental design with particle size and encapsulation efficiency as responses. Optimized liposomes showed small size (157.5 ± 0.27 nm), zeta potential (-24.14 ± 0.25 mV), low PDI (0.149 ± 0.002), high encapsulation efficiency (92.85 ± 0.06%), and drug loading (10.48 ± 0.17%). Hydroxyapatite binding and <i>in vivo</i> fluorescence imaging confirmed enhanced bone affinity and accumulation. Quantitative pharmacokinetic analysis demonstrated prolonged systemic exposure of Icariin-TC-DSPE-PEG-L compared with free icariin and non-targeted liposomes, indicating improved circulation and bioavailability. In osteoporotic rats, the formulation significantly improved bone microstructure, increased bone mass, and regulated bone homeostasis. The TC/PEG co-modified liposomes effectively overcame limitations of icariin's delivery, thus offering a novel therapeutic strategy for osteoporosis. Notwithstanding, long-term toxicity of TC/PEG co-modified liposomes and mechanisms underlying its therapeutic efficacy will be explored in the not-too-distant future.