Bone-Targeted Biomimetic Nanogels Re-Establish Osteoblast/Osteoclast Balance to Treat Postmenopausal Osteoporosis

Insufficient bone formation and excessive bone resorption caused by estrogen deficiency are the major factors resulting in the incidence of postmenopausal osteoporosis (PMOP). The existing drugs usually fail to re-establish the osteoblast/osteoclast balance from both sides and generate side-effects owing to the lack of bone-targeting ability. Here, engineered cell-membrane-coated nanogels PNG@mR&C capable of scavenging receptor activator of nuclear factor-kappa B ligand (RANKL) and responsively releasing therapeutic PTH 1-34 in the bone microenvironment are prepared from RANK and CXCR4 overexpressed bone mesenchymal stem cell (BMSC) membrane-coated chitosan biopolymers. The CXCR4 on the coated-membranes confer bone-targeting ability, and abundant RANK effectively absorb RANKL to inhibit osteoclastogenesis. Meanwhile, the release of PTH 1-34 triggered by osteoclast-mediated acid microenvironment promote osteogenesis. In addition, the dose and frequency are greatly reduced due to the smart release property, prolonged circulation time, and bone-specific accumulation. Thus, PNG@mR&C exhibits satisfactory therapeutic effects in the ovariectomized (OVX) mouse model. This study provides a new paradigm re-establishing the bone metabolic homeostasis from multitargets and shows great promise for the treatment of PMOP. Genetically manipulated bone mesenchymal stem cell (BMSC) membrane is extracted and coated on chitosan-based nanogels containing PTH 1-34 to construct biomimetic nanogels. Abundant membrane CXCR4 confers these nanogels bone-targeting ability. The RANK confers them receptor activator of nuclear factor-kappa B ligand (RANKL) absorbing ability to inhibit osteoclastogenesis. Osteoclast-mediated acid microenvironment contributes to PTH 1-34 release, thus promoting osteogenic differentiation and re-establishing osteoblast/osteoclast balance to treat postmenopausal osteoporosis (PMOP).image