Stage-specific biomimetic nanoparticles reprogram osteoblast-adipocyte equilibrium for targeted osteoporosis therapy

Cell membrane-camouflaged nanoparticles have emerged as powerful tools for targeted drug delivery; however, current strategies typically utilize membranes from static cell states, overlooking the dynamic functional evolution that occurs during lineage commitment. Here, we established a stepwise osteogenic differentiation model for BMSCs and isolated cell membranes from distinct stages of this process to construct a series of cell membrane-camouflaged mesoporous silica nanoparticles (CM-MSNs). Proteomic profiling revealed stage-dependent remodeling of membrane protein composition, with early osteogenic (EO) stage membranes uniquely enriched in phosphatases and cadherins. Functional evaluations showed stage-dependent activity among CM-MSNs, and EO membrane-camouflaged nanoparticles (EO-MSNs) exhibited the strongest capacity to promote calcium deposition and enhance BMSC osteogenesis in vitro via the Wnt/β-catenin signaling pathway. In a rat model of osteoporosis, EO-MSN exhibited prolonged circulation time, precise bone-specific accumulation, and potent anti-osteoporotic efficacy. Collectively, our findings suggest that utilizing stage-specific cell membranes offers a novel strategy to remodel the osteoporotic microenvironment by modulating the osteoblast-adipocyte equilibrium.