Stem cell membrane-coated rough mesoporous silica nanoparticles for enhanced osteogenic differentiation and bone repair via dexamethasone delivery

Mesoporous silica nanoparticles (MSNs) have been demonstrated to promote osteoblast differentiation; however, the unclear impact of their surface roughness on osteogenesis, coupled with inadequate targeting capability and suboptimal therapeutic outcomes, presents major challenges. Herein, we developed a biomimetic nanoplatform, CM@DEX-R-MSN, by coating dexamethasone (DEX) loaded-rough MSN (R-MSN) with mesenchymal stem cell (MSC) membranes (CM) to enhance osteogenic differentiation of MSCs for improved bone regeneration. The CM@DEX-R-MSN showed retained rough surfaces with a hydrodynamic diameter of 164.35 ± 5.81 nm, a Zeta potential of -11.98 ± 1.37 mV with good MSC membrane integrity, negligible cytotoxicity both<i>in vitro</i>and<i>in vivo</i>. CM@DEX-R-MSN exhibited significantly enhanced MSC internalization compared to uncoated MSN. They markedly upregulated alkaline phosphatase activity, osteogenic markers, and mineralization nodule formation<i>in vitro</i>. In bone defect model established in rabbits, CM@DEX-R-MSN restored bone volume and prolonged retention at the defect site. More importantly, we experimentally observed that both R-MSN and CM-coated nanoparticles exhibited superior osteogenic differentiation effects compared to conventional MSNs and non-coated counterparts, respectively-with CM@DEX-R-MSN demonstrating the most potent efficacy. Our results demonstrated that CM@DEX-R-MSN synergistically integrates MSC membrane-mediated homotypic targeting, nanotopography of R-MSN, and DEX-driven osteogenic differentiation, offering a promising targeted therapeutic strategy for bone regeneration. Their enhanced biocompatibility, osteogenic efficacy, and sustained retention underscore its translational potential for orthopedic applications.