Novel bone-targeting nano-systems with red blood cell membrane carrying siRNA and oleanolic acid

Disuse osteoporosis is a significant clinical challenge lacking targeted therapies. This study developed a bone-targeted nanoplatform for osteoblast therapy. A candidate drug was first screened using network pharmacology. Subsequently, siRNA-loaded nanoparticles with a ssPBAE/PLGA/OA (PPO) core were synthesized by ultrasonic emulsification. These were further cloaked with a red blood cell membrane (RBCM) functionalized with a bone-homing (AspSerSer) 6 peptide to create the final targeted (DSS) 6 -RBCM-PPOS nano particle through ultrasonic coating. The nanoparticles were thoroughly characterized and demonstrated high drug loading (95%), efficient cellular uptake, and significant lysosomal escape in MC3T3-E1 osteoblasts. In vitro microgravity cell model, nanoparticles exhibited better ROS clearance and promoting osteogenesis ability. In a disuse osteoporosis mouse model induced by botulinum toxin-induced hindlimb paralysis, treatment with the targeted nanoparticles showed good biocompatibility and significantly improved trabecular bone density and microstructure compared to controls, as confirmed by micro-CT analysis. In conclusion, we successfully developed a multifunctional nanoplatform that exhibits excellent in vitro performance and significant therapeutic efficacy in restoring bone loss, highlighting its great potential for targeted osteoblast therapy in disuse osteoporosis.