Engineering L-Arg@ZIF-8 nanoparticles to modulate the immune-osteogenic-angiogenic microenvironment for accelerated bone fracture healing

Bone fracture healing requires coordinated regulation of osteogenesis, angiogenesis, and immune homeostasis within a dynamically evolving microenvironment. However, current biomaterials rarely integrate these three regulatory dimensions. Herein, we engineered L-arginine-loaded zeolitic imidazolate framework-8 (L-Arg@ZIF-8) nanoparticles to remodel the immune-osteogenic-angiogenic microenvironment and accelerate fracture healing. L-Arg@ZIF-8 nanoparticles exhibited uniform morphology, positive surface charge, and stable L-Arg incorporation, enabling efficient cellular uptake and sustained bioactivity. Using two physiologically relevant 3D co-culture spheroid models (osteoblast-macrophage and osteoblast-endothelial), we demonstrated that L-Arg@ZIF-8 promotes osteogenic differentiation, endothelial activation and the upregulation of angiogenic markers, and strengthens osteogenesis-angiogenesis coupling. Bulk transcriptomic profiling further revealed activation of regenerative pathways, including PI3K-Akt and Wnt signaling, along with coordinated modulation of cytokine-receptor interactions and immune-related remodeling programs. In vivo, L-Arg@ZIF-8 markedly accelerated fracture repair in a rat rib fracture model, characterized by enhanced callus formation, increased bone mineral density, greater trabecular thickness, and a significantly elevated mineral apposition rate. Histological and immunofluorescence analyses confirmed upregulation of key osteogenic markers (OPN, OSX) at the fracture site. Together, these findings demonstrate that L-Arg@ZIF-8 functions as a bioengineered microenvironment-modulating nanoplatform that orchestrates immune regulation, osteogenesis, and angiogenesis to promote efficient fracture healing. This strategy offers a promising therapeutic avenue for translational management of complex fractures.