EphB4-decorated biomimetic nanoparticles enhance osteoclast targeting and therapeutic effect in osteoporosis

The therapeutic efficacy of osteoporosis (OP) treatments is often limited by inadequate cellular precision and poor accumulation within the bone microenvironment. Although synthetic nanoparticles have been developed to address these challenges, they commonly face biological barriers such as rapid systemic clearance, inefficient transendothelial transport, and limited affinity for the complex bone niche. Here, we report on a biomimetic nanobiotechnology platform that integrates biological recognition with precision polymer engineering to overcome these limitations. We engineered a core–shell nanostructure consisting of a bilirubin-loaded Poly D L-Lactide-co-glycolide (PLGA) core cloaked with genetically modified osteoblast (OB)-derived membranes overexpressing the Ephrin type-B receptor 4 (EphB4) receptor. This biomimetic nanoparticle (NP) exploits the endogenous EphB4–EphrinB2 (EFNB2) signaling axis to achieve selective recognition and preferential uptake by EFNB2-expressing osteoclasts (OCs), displaying significantly higher internalization in OCs compared with mesenchymal stem cells (MSC), macrophages (Mφ), and OBs in vitro. Furthermore, the cell-membrane corona enables efficient transendothelial migration under inflammatory conditions, facilitating targeted delivery to OCs beyond the vascular endothelium. In vitro molecular analyses demonstrated that receptor-mediated NP uptake significantly suppressed key osteoclastogenic regulators, including nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), cathepsin K, and matrix metalloproteinase-9 (MMP-9). In a preclinical OP model, systemic administration resulted in bone-specific accumulation and robust restoration of trabecular microarchitecture and bone mineral density (BMD). Collectively, this work demonstrates that interfacial nanoengineering can translate complex receptor-guided biological interactions into stable, high-performance nanotherapeutics for the precision treatment of skeletal disorders.