Bone-targeting cell membrane-engineered CaCO3-based nanoparticles restore local bone homeostasis for microenvironment-responsive osteoporosis treatment

Osteoporosis is a common bone disease characterized by the systemic disruption of hone homeostasis, where the imbalance between bone resorption and formation causes deterioration of bone structure and bone mass loss. Targeted restoration of bone hemostasis has thus become a promising strategy for osteoporosis treatment. For this purpose, we report a bone-targeted nanoformulation based on CaCO 3 nanomaterials, which could be activated in the acidic osteoporotic microenvironment and cooperatively regulate the activity of osteoclasts and osteoblasts to reverse bone deterioration. Herein, a clinical antiosteoporosis drug β-estradiol (E2) is first biomineralized using CaCO 3 to form physiologically stable nanocores. Meanwhile, azido groups are introduced onto MC3T3-E1 cells through incubation with AC 4 ManNAz. The azido-tagged MC3T3-E1 cell membranes are extracted for the camouflaging of the CaCO 3 @E2 nanocores to enhance their in vivo stability and availability, while also enabling the surface modification of bone-targeting dibenzocyclooctyne-tagged alendronate moieties via copper-free click reaction. After the selective deposition into acidic osteoporotic bone tissues, the CaCO 3 @E2 cores would be spontaneously degraded to release E2 and Ca 2+ ions, which would systematically inhibit the activity of osteoclasts while promoting osteoblast-mediated new bone formation, eventually ameliorating the osteoporosis symptoms. This study offers an effective approach for osteoporosis treatment in the clinics.